To see the other types of publications on this topic, follow the link: Agoniste - Antagoniste.
Journal articles on the topic 'Agoniste - Antagoniste'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Agoniste - Antagoniste.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Carpenter, A., J. Duchateau, and K. Hainaut. "Signification Fonctionnelle de la Coactivation Agoniste-Antagoniste Dans Les Mouvements Rapides de Flexion Plantaire." Archives of Physiology and Biochemistry 103, no. 3 (January 1, 1995): C133. http://dx.doi.org/10.3109/13813459509037341.
Full text
2
Schwartz, Jean-Charles, Jeanne-Marie Lecomte, and Christian Caussé. "Efficacité anticataplectique de pitolisant, nouvel antagoniste/agoniste inverse du récepteur H3 de l’histamine chez des patients narcoleptiques." Médecine du Sommeil 14, no. 1 (March 2017): 48. http://dx.doi.org/10.1016/j.msom.2017.01.091.
Full text
3
Pai, Howard Huaihan, Tom Pickles, Mira Keyes, Stuart Jones, Rachel E. McDonald, Mary Lesperance, and Eric Berthelet. "Randomized study evaluating testosterone recovery using short-versus long-acting luteinizing hormone releasing hormone agonists." Canadian Urological Association Journal 5, no. 3 (April 4, 2013): 173. http://dx.doi.org/10.5489/cuaj.639.
Full textAbstract:
Introduction: We sought to compare the rate of return of testosteronelevels and sexual function in men with prostate cancerreceiving longer acting, 3-month preparation of luteinizing hormone-releasing hormone agonist (L-LHRH-A) versus shorter acting,1-month preparation of luteinizing hormone-releasing hormoneagonist (S-LHRH-A).Methods and Materials: Men with low to intermediate risk localizedprostate cancer were randomized to either L-LHRH-A (2-3 monthduration LHRH-A) or S-LHRH-A (6-1 month duration LHRH-A) ofandrogen suppression therapy (AST) and prostate brachytherapyusing iodine-125 radioisotopes. Serum total testosterone levels andPSA were recorded every 2 months for 2 years.Results: A planned target sample size of 100 was not achieveddue to insufficient accrual. A total of 55 patients were randomizedand 46 were used for analysis. The median time to recovery oftestosterone to baseline levels (calculated from end of AST) was 8and 4 months in the L-LHRH-A and S-LHRH-A arms, respectively(p = 0.268). The median time to testosterone recovery to lower limitof reference range was 4 and 2 months respectively (p = 0.087).Interpretation: This randomized study, which failed to reachaccrual target, showed a trend towards more rapid recovery oftestosterone levels using shorter acting LHRH-A. Another randomizedstudy would be required to validate these findings. Currently,there is insufficient evidence to recommend the use of shorteracting LHRH-A as a means of providing more rapid recovery oftestosterone levels.Introduction : Nous avons voulu comparer la vitesse de retourdes taux de testostérone et de la fonction sexuelle chez des hommesatteints d’un cancer de la prostate recevant un agoniste de laLHRH à longue durée d’action pendant 3 mois ou un agoniste dela LHRH à courte durée d’action pendant 1 mois.Matériel et méthodologie : Des hommes atteints d’un cancer dela prostate localisé avec risque faible à intermédiaire ont été randomiséspour recevoir soit un agoniste de la LHRH à longue duréed’action (2 doses trimestrielles) soit un antagoniste de la LHRHà courte durée d’action (6 doses mensuelles) comme traitementantiandrogène et une brachythérapie prostatique avec des radioisotopesde l’iode 125. Les taux sériques de testostérone totale etd’APS ont été notés tous les 2 mois pendant 2 ans.Résultats : L’échantillon prévu au départ de 100 patients n’apu être obtenu en raison d’un recrutement insuffisant. Au total,55 patients ont été randomisés et 46 ont été inclus dans les analyses.L’intervalle médian de retour à des taux normaux de testostérone(calculés à partir de la fin du traitement antiandrogène) étaitde 8 et 4 mois dans les groupes sous agoniste de la LHRH à longueet à courte durée d’action, respectivement (p = 0,268). L’intervallemédian requis pour que les taux de testostérone atteignent la limiteinférieure des valeurs de référence était de 4 et 2 mois, respectivement(p = 0,087).Interprétation : Cette étude randomisée, où on n’a pas réussi àobtenir le nombre de patients voulu, a montré une tendance vers unretour plus rapide des taux de testostérone avec un traitement paragoniste de la LHRH à courte durée d’action. Une autre étude randomiséeserait nécessaire pour valider ces résultats. Actuellement,on ne dispose pas de suffisamment de données pour recommanderun agoniste de la LHRH à courte durée d’action comme moyenpour ramener les taux de testostérone plus rapidement à la normale.
4
Schlezinger, Jennifer J., Wendy Heiger-Bernays, and Thomas F. Webster. "Predicting the Activation of the Androgen Receptor by Mixtures of Ligands Using Generalized Concentration Addition." Toxicological Sciences 177, no. 2 (July 8, 2020): 466–75. http://dx.doi.org/10.1093/toxsci/kfaa108.
Full textAbstract:
Abstract Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data—full/full agonist, full/partial agonist, and full agonist/antagonist—as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists.
5
Krenz, Wulf D., Don Nguyen, Nivia L. Pérez-Acevedo, and Allen I. Selverston. "Group I, II, and III mGluR Compounds Affect Rhythm Generation in the Gastric Circuit of the Crustacean Stomatogastric Ganglion." Journal of Neurophysiology 83, no. 3 (March 1, 2000): 1188–201. http://dx.doi.org/10.1152/jn.2000.83.3.1188.
Full textAbstract:
We have studied the effects of group I, II, and III metabotropic glutamate receptor (mGluR) agonists on rhythm generation by the gastric circuit of the stomatogastric ganglion (STG) of the Caribbean spiny lobster Panulirus argus. All mGluR agonists and some antagonists we tested in this study had clear and distinct effects on gastric rhythm generation when superfused over combined oscillating or blocked silent STG preparations. A consistent difference between group I agonists and group II and III agonists was that group I agonists acted excitatory. The group I-specific agonists l-quisqualic acid and ( S)-3,5-dihydroxyphenylglycine, as well as the nonspecific agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid accelerated ongoing rhythms and could induce gastric rhythms in silent preparations. The group II agonist (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-I) and the group III agonist l(+)-2-amino-4-phosphonobutyric acid (l-AP4) slowed down or completely blocked ongoing gastric rhythms and were without detectable effect on silent preparations. The action of L-CCG-I was blocked partially by the group-II-specific antagonist, (RS)-1-amino-5-phosphonoindan-1-carboxylic acid [(RS)APICA], and the group-III-specific antagonist (RS)-α-methyl-4-phosphonophenylglycine completely blocked the action of l-AP4. Besides its antagonistic action, the group-II-specific antagonist (RS)APICA had a remarkably strong apparent inverse agonist action when applied alone on oscillating preparations. The action of all drugs was dose dependent and reversible, although recovery was not always complete. In our experiments, the effects of none of the mGluR-specific agonists were antagonized or amplified by the N-methyl-d-aspartate (NMDA)-receptor-specific antagonistd(−)-2-amino-5-phosphonopentanoic acid, excluding the contamination of responses to mGluR agonists by nonspecific cross-reactivity with NMDA receptors. Picrotoxin did not prevent the inhibitory action of L-CCG-I and l-AP4. We conclude that mGluRs, probably similar to those belonging to groups I, II, and III described in mammals, may play a role as modulators of gastric circuit rhythm generation in vivo.
6
Lecendreux, Michel, Giuseppe Plazzi, Patricia Franco, Philippe Robert, Thierry Duvauchelle, and Jeanne-Marie Lecomte. "Tolérance et pharmacocinétique de pitolisant (Wakix®), un antagoniste/agoniste inverse du récepteur à histamine H3, chez 24 enfants narcoleptiques." Médecine du Sommeil 14, no. 1 (March 2017): 10. http://dx.doi.org/10.1016/j.msom.2017.01.129.
Full text
7
Grider, J. R., and G. M. Makhlouf. "Identification of opioid receptors on gastric muscle cells by selective receptor protection." American Journal of Physiology-Gastrointestinal and Liver Physiology 260, no. 1 (January 1, 1991): G103—G107. http://dx.doi.org/10.1152/ajpgi.1991.260.1.g103.
Full textAbstract:
Opioid receptors on isolated gastric smooth muscle cells were characterized pharmacologically by a technique in which synthetic selective opioid agonists and antagonists were used to protect and thus enrich a specific receptor type while all other receptors were inactivated by N-ethylamaleimide. Treatment of the cells with the selective mu-receptor agonist DAGO or antagonist CTAP preserved only the response to DAGO; treatment with the selective delta-receptor agonist DPDPE or antagonist naltrindole preserved only the response to DPPE; and treatment with the selective kappa-receptor agonist U50,488H or antagonist nor-binaltorphimine preserved only the response to U50,488H. The results established the presence of distinct kappa-, delta-, and mu-opioid receptors capable of mediating contraction of isolated gastric muscle cells. The pattern of interaction of endogenous opioid peptides with protected receptors implied that dynorphin-(1-13) and Met-enkephalin were selective agonists for kappa- and delta-opioid receptors, respectively, and Leu-enkephalin a preferential agonist of mu-opioid receptors. The results were confirmed by a reverse approach in which opioid receptors were inactivated by site-directed irreversible antagonists. beta-Funaltrexamine, a mu-selective antagonist, abolished the response to mu-receptor agonists, whereas beta-chlornaltrexamine, a mu- and kappa-selective antagonist, abolished the response to mu-receptor agonists and partially inhibited the response to kappa-receptor agonists.
8
Sakkiah, Sugunadevi, Chandrabose Selvaraj, Wenjing Guo, Jie Liu, Weigong Ge, Tucker A. Patterson, and Huixiao Hong. "Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations." International Journal of Molecular Sciences 22, no. 17 (August 29, 2021): 9371. http://dx.doi.org/10.3390/ijms22179371.
Full textAbstract:
Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17β-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses.
9
Wilson, Kristy J., Christopher P. Mill, Richard M. Gallo, Elizabeth M. Cameron, Henry VanBrocklin, Jeffrey Settleman, and David J. Riese. "The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist." Biochemical Journal 443, no. 1 (March 14, 2012): 133–44. http://dx.doi.org/10.1042/bj20110921.
Full textAbstract:
The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2β (neuregulin 2β) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2β/Q43L may be an ErbB4 antagonist. NRG2β/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2β/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2β. In addition, NRG2β stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2β stimulates greater Akt phosphorylation than does NRG2β/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2β and NRG2β/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2β/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2β/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2β/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2β/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics.
10
Fong, Tung Ming, Ruey-Ruey C. Huang, Hong Yu, Dennis Underwood, Margaret A. Cascieri, Catherine D. Strader, and Christopher J. Swain. "Mutational analysis of neurokinin receptor function." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 860–65. http://dx.doi.org/10.1139/y95-118.
Full textAbstract:
The interactions of the NK1 receptor with peptide agonists or nonpeptide antagonists have been investigated by site-directed mutagenesis and computer modeling. At least 10 residues in the extracellular and transmembrane regions of the receptor are required for the binding of many peptide agonists. The C-terminal amide of peptide agonists is likely to be bound near Asn-85. Residues likely to be involved in the subsequent receptor activation include Glu-78 and Tyr-205. The binding site for nonpeptide antagonists can be defined by at least five residues in transmembrane helices 4–7, and primary contacts between key residues and quinuclidine antagonists have been assigned based on CP-96,345 and its analogs. Analyses of the wild-type and mutant NK1 and NK2 receptors, intact and truncated peptides, and various antagonists suggest that the agonist and antagonist binding sites overlap spatially, even though agonists and antagonists do not interact with the same set of residues on the receptor. Mapping the ligand binding site not only allows us to better understand the ligand–receptor interaction and antagonism but also leads to a refined three-dimensional model of the NK1 receptor.Key words: receptor, substance P, agonist, antagonist, mutagenesis.
11
Hopfner, Franziska, Mette Wod, Günter U. Höglinger, Morten Blaabjerg, Thomas W. Rösler, Gregor Kuhlenbäumer, Kaare Christensen, Günther Deuschl, and Anton Pottegård. "Use of β2-adrenoreceptor agonist and antagonist drugs and risk of Parkinson disease." Neurology 93, no. 2 (May 24, 2019): e135-e142. http://dx.doi.org/10.1212/wnl.0000000000007694.
Full textAbstract:
ObjectiveTo verify the previously reported association between long-term use of β2-adrenoreceptor (β2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively.MethodsWe obtained odds ratios (ORs) associating time of β2AR agonist and antagonist use with PD risk in nationwide Danish health registries.ResultsWe included 2,790 patients with PD and 11,160 controls. Long-term β2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40–0.82) in this cohort. Unexpectedly, short-term β2AR agonist use was equally associated (OR 0.64, 95% CI 0.42–0.98). Because β2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37–0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59–1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25–0.67) were also inversely associated with PD. Increased PD risk was not found for all β2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use.ConclusionWe confirmed β2AR agonist use to be associated with reduced PD risk and β2AR antagonist use with increased PD risk. However, our data indicate the association of β2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of β2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists and antagonists and PD risk.
12
Hirayama, Shigeto, and Hideaki Fujii. "δ Opioid Receptor Inverse Agonists and their In Vivo Pharmacological Effects." Current Topics in Medicinal Chemistry 20, no. 31 (December 3, 2020): 2889–902. http://dx.doi.org/10.2174/1568026620666200402115654.
Full textAbstract:
The discovery of δ opioid receptor inverse agonist activity induced by ICI-174,864, which was previously reported as an δ opioid receptor antagonist, opened the door for the investigation of inverse agonism/constitutive activity of the receptors. Various peptidic or non-peptidic δ opioid receptor inverse agonists have since been developed. Compared with the reports dealing with in vitro inverse agonist activities of novel compounds or known compounds as antagonists, there have been almost no publications describing the in vivo pharmacological effects induced by a δ opioid receptor inverse agonist. After the observation of anorectic effects with the δ opioid receptor antagonism was discussed in the early 2000s, the short-term memory improving effects and antitussive effects have been very recently reported as possible pharmacological effects induced by a δ opioid receptor inverse agonist. In this review, we will survey the developed δ opioid receptor inverse agonists and summarize the possible in vivo pharmacological effects by δ opioid receptor inverse agonists. Moreover, we will discuss important issues involved in the investigation of the in vivo pharmacological effects produced by a δ opioid receptor inverse agonist.
13
BERREVOETS, Cor A., Arzu UMAR, Jan TRAPMAN, and Albert O. BRINKMANN. "Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)." Biochemical Journal 379, no. 3 (May 1, 2004): 731–38. http://dx.doi.org/10.1042/bj20031456.
Full textAbstract:
Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)- and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonist-bound AR has a preference for N-CoR. The AR mutation T877A (Thr877→Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of N-CoR. The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.
14
Colson, James. "Office-Based Opioid Dependence Treatment." July 2012 3S;15, no. 3S;7 (July 14, 2012): ES231—ES236. http://dx.doi.org/10.36076/ppj.2012/15/es231.
Full textAbstract:
Background: Opioid misuse and abuse occurring in association with the treatment of chronic non-cancer pain are not new phenomena, but their increasing prevalence in recent years is unprecedented. Advancements in pharmaceutical technologies have provided opioid-related drugs, which lack the pure mu agonist activity characteristic of the typical opioid congeners. This absent or altered mu receptor activity imparts an opioid receptor antagonistic or partial agonistic pharmacologic action, which serves to modulate the development of opioid-induced tolerance and physical dependence and facilitate detoxification and withdrawal from opioids. Opioid antagonists and partial agonists are being used in abuse deterrent strategy regimens to prevent opioid tolerance and the development of dependence, as well as in the management of opioid detoxification and treatment of withdrawal. The specific opioid antagonists and partial agonists used in these various therapeutic modalities will be the focus of this review. Objectives: Evaluate the comparative therapeutic utility of opioid antagonists and partial agonists in preventing the development of opioid tolerance and treating opioid dependence, detoxification, and withdrawal. A primary focus is the use of opioid antagonists and partial agonists within an office-based practice. Methods: A narrative review of the current literature involving the therapeutic use of opioid antagonists and partial agonists in the management of opioid tolerance, dependence, detoxification, and withdrawal. A computerized literature search in the PubMed, EMBASE, BioMed, and Cochrane Library review databases from 2008 through 2010 was performed. This search included systematic and narrative reviews, prospective and retrospective studies, as well as cross-references from bibliographies of notable primary and review articles and abstracts from scientific meetings. US Food and Drug Administration records and pharmaceutical manufacturers’ product literature were also used in the search. Conclusion: Opioid dependency, whether it results from the misuse or abuse of prescription or street drugs, continues to be a significant public health issue. Passage of DATA 2000 and US Food and Drug Administration approval of buprenorphine and buprenorphine/ naloxone has revolutionized opioid dependence therapy. The traditional addiction medicine therapy regimen of methadone maintenance, with its inherent legal limitations and restrictions, has been challenged by an office-based dependence practice with buprenorphine serving as a prominent therapeutic tool. Key words: opioid antagonist, opioid partial agonist, tolerance, dependence, detoxification, withdrawal, hyperalgesia, buprenorphine, suboxone, naloxone, naltrexone, methylnaltrexone, nalmefene, tramadol, butorphanol, nalbupine, pentazocine.
15
Regoli, Domenico, Anna Rizzi, Stephan I. Perron, and Fernand Gobeil. "Classification of Kinin Receptors." Biological Chemistry 382, no. 1 (January 6, 2001): 31–35. http://dx.doi.org/10.1515/bc.2001.005.
Full textAbstract:
Abstract This minireview is divided into three parts: the first part refers to the characterization and classification of kinin receptors using agonists and antagonists in isolated tissues (classical pharmacology). Two kinin receptors have been considered on the basis of their distinct pharmacology, namely the B1 receptor of the rabbit aorta (rank order of potency of agonists: LysdesArg9BK > desArg9BK >= LysBK>BK; apparent affinities of antagonists Lys[Leu8]desArg9BK (pIC50 8.4 ) > [Leu8]desArg9BK (pIC50 7.4)>>>HOE 140, a B2 receptor antagonist, pIC50<5.0), and the B2 receptor of the rabbit jugular vein (potency of agonists: LysBK = BK>>> LysdesArg9BK = desArg9BK and HOE 140 (pIC50 9.0)>>>Lys[Leu8]desArg9BK, pIC50<5.0). The second part describes speciesrelated B1receptor subtypes, demonstrated by different pharmacological profiles of agonists and antagonists: human, rabbit and pig subtypes (LysdesArg9BK >> desArg9B K and Lys[Leu8]desArg9BK > [Leu8]desArg9BK) and dog, rat, mouse and hamster B1 receptors (desArg9BK = LysdesArg9BK and [Leu8]desArg9BK = Lys[Leu8]desArg9BK). Affinities of agonists and antagonists in some species (man, rabbit, pig) are significantly increased (at least 10-fold) by the presence of a Lys at their Nterminus. The last part describes species-related B2 receptor subtypes supported by results obtained with non-peptide receptor agonists (FR 190997) and antagonists (FR 173657). While BK acts as a full agonist in man, rabbit and pig, FR 190997 behaves as a full agonist on human, as partial agonist on rabbit, and as pure antagonist on pig B2 receptors. Various hypotheses are considered to interpret these findings.
16
Niedernberg, Anke, Sorin Tunaru, Andree Blaukat, Bruce Harris, and Evi Kostenis. "Comparative Analysis of Functional Assays for Characterization of Agonist Ligands at G Protein-Coupled Receptors." Journal of Biomolecular Screening 8, no. 5 (October 2003): 500–510. http://dx.doi.org/10.1177/1087057103257555.
Full textAbstract:
A variety of functional assays are available for agonist or antagonist screening of G protein-coupled receptors (GPCRs), but it is a priori not predictable which assay is the most suitable to identify agonists or antagonists of GPCRs with therapeutic value in humans. More specifically, it is not known how a given set of GPCR agonists compares in different functional assays with respect to potency and efficacy and whether the level of the signaling cascade that is analyzed has any impact on the detection of agonistic responses. To address this question, the authors used the recently cloned human S1P5 receptor as a model and compared a set of 3 lipid ligands (sphingosine 1-phosphate [S1P], dihydro sphingosine 1-phosphate [dhS1P], and sphingosine) in 5 different functional assays: GTPγS binding, inhibition of adenylyl cyclase activity, mobilization of intracellular Ca2+ via the FLIPR and aequorin technology, and MAP kinase (ERK1/2) activation. S1P induced agonistic responses in all except the ERK1/2 assays with EC50 values varying by a factor of 10. Whereas dhS1P was identified as a partial agonist in the GTPγS assay, it behaved as a full agonist in all other settings. Sphingosine displayed partial agonistic activity exclusively in GTPγS binding assays. The findings suggest that assays in a given cellular background may vary significantly with respect to suitability for agonist finding and that ligands producing a response may not readily be detectable in all agonist assays. ( Journal of Biomolecular Screening 2003:500-510)
17
Kenakin, Terry. "Agonists, partial agonists, antagonists, inverse agonists and agonist/antagonists?" Trends in Pharmacological Sciences 8, no. 11 (November 1987): 423–26. http://dx.doi.org/10.1016/0165-6147(87)90229-x.
Full text
18
Lu, Nan, Fancui Meng, Jing Yuan, Lei Liu, Yanshi Wang, Lingjun Li, Tong Zhao, Weiren Xu, Lida Tang, and Youjun Xu. "Characterizing the interaction modes of PAR4 receptor with agonist and antagonist by molecular simulation approach." Journal of Theoretical and Computational Chemistry 18, no. 02 (March 2019): 1950008. http://dx.doi.org/10.1142/s0219633619500081.
Full textAbstract:
Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.
19
Zhang, L., Z. F. Gu, T. Pradhan, R. T. Jensen, and P. N. Maton. "Characterization of opioid receptors on smooth muscle cells from guinea pig stomach." American Journal of Physiology-Gastrointestinal and Liver Physiology 262, no. 3 (March 1, 1992): G461—G469. http://dx.doi.org/10.1152/ajpgi.1992.262.3.g461.
Full textAbstract:
On the basis of opioid-stimulated contraction of dispersed gastric smooth muscle cells it has been suggested that these cells possess opioid receptors of three subtypes: kappa (kappa), mu (mu), and delta (delta). We have used selective peptidase-resistant radioligands, agonists and antagonists, to examine receptor subtypes on dispersed gastric smooth muscle cells from guinea pigs prepared by collagenase digestion. The kappa-agonist U-50488H, the mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO), and the delta-agonist [D-Pen2,Pen5]enkephalin (DPDPE) each caused muscle contraction. The concentrations required to caused half-maximal contraction were U50488H (6 pM) greater than DAGO (13 pM) greater than DPDPE (6 nM). The abilities of these agonists to inhibit binding of [3H]U-69593 (kappa-preferring) by 50% were U50488H (43 nM) greater than DAGO (43 microM) greater than DPDPE (200 microM). Their abilities to inhibit binding of [3H]naloxone (mu-preferring) by 50% were DAGO (0.2 microM) greater than U50488H (10 microM) greater than DPDPE (greater than 100 microM). No binding could be detected with the delta-selective ligand [3H]DPDPE. The kappa-preferring antagonist Mr2266 (10 nM) preferentially inhibited contraction stimulated by the kappa-agonist U50488H, and naltrexone (10 nM) (mu-selective antagonist) preferentially inhibited contraction stimulated by the mu-agonist DAGO. ICI 174864 (200 microM; delta-selective antagonist) had no effect on contraction stimulated by mu-, kappa-, or delta-agonists. Contraction stimulated by the delta-agonist DPDPE was inhibited by both kappa- and mu-receptor antagonists. Studies on the effect of the antagonists on binding of [3H]naloxone and [3H]U69593 also provided evidence for kappa- and mu-sites but nor for delta-sites.(ABSTRACT TRUNCATED AT 250 WORDS)
20
Perez Diaz, Noelia, Lisa A. Lione, Victoria Hutter, and Louise S. Mackenzie. "Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery." International Journal of Molecular Sciences 22, no. 6 (March 19, 2021): 3158. http://dx.doi.org/10.3390/ijms22063158.
Full textAbstract:
Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARβ/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ-regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL-6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL-6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS-induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co-incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.
21
Smith, Emery, Peter Chase, Colleen M. Niswender, Thomas J. Utley, Douglas J. Sheffler, Meredith J. Noetzel, Atin Lamsal, et al. "Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4)." Journal of Biomolecular Screening 20, no. 7 (April 15, 2015): 858–68. http://dx.doi.org/10.1177/1087057115581770.
Full textAbstract:
Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer’s disease and other disorders involving impaired cognitive function. In an attempt to identify orthosteric and allosteric modulators of the muscarinic acetylcholine receptor M4 (M4), we developed a homogenous, multiparametric, 1536-well assay to measure M4 receptor agonism, positive allosteric modulation (PAM), and antagonism in a single well. This assay yielded a Z′ of 0.85 ± 0.05 in the agonist, 0.72 ± 0.07 in PAM, and 0.80 ± 0.06 in the antagonist mode. Parallel screening of the M1 and M5 subtypes using the same multiparametric assay format revealed chemotypes that demonstrate selectivity and/or promiscuity between assays and modalities. This identified 503 M4 selective primary agonists, 1450 PAMs, and 2389 antagonist hits. Concentration-response analysis identified 25 selective agonists, 4 PAMs, and 41 antagonists. This demonstrates the advantages of this approach to rapidly identify selective receptor modulators while efficiently removing assay artifacts and undesirable compounds.
22
Hogendorf, Agata, Adam S. Hogendorf, Rafał Kurczab, Grzegorz Satała, Bernadeta Szewczyk, Paulina Cieślik, Gniewomir Latacz, et al. "N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential." Molecules 26, no. 15 (July 29, 2021): 4605. http://dx.doi.org/10.3390/molecules26154605.
Full textAbstract:
A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
23
Kaler, Gregory, Michael Otto, Alex Okun, and Ilya Okun. "Serotonin Antagonist Profiling on 5HT2A and 5HT2C Receptors by Nonequilibrium Intracellular Calcium Response Using an Automated Flow-Through Fluorescence Analysis System, HT-PS®0." Journal of Biomolecular Screening 7, no. 3 (June 2002): 291–301. http://dx.doi.org/10.1177/108705710200700313.
Full textAbstract:
Characterization of the potencies of agonists and antagonists in cell-based assays can be complicated by nonequilibrium conditions of functional response. We assessed the potencies of a series of serotonin (5HT) antagonists by inhibition of intracellular calcium response in HEK 293 cells expressing 5HT2A or 5HT2C receptors. An automated system, HT-PS 100, was used to profile the antagonists in two experimental setups: coadministration of agonist and antagonist to cells and preincubation of the cells with antagonist prior to agonist administration. We showed that the antagonist potencies (pIC50 values) determined in the preincubation configuration were close to or exceeded those measured in the coadministration configuration. Closeness of the potencies determined in the two configurations supposedly reflected a rapid antagonist-receptor equilibration, whereas a significantly higher preincubation potency implied slow antagonist dissociation from the receptor. Schild analysis of the inhibition of serotonin-induced cell response by a competitive 5HT2A antagonist, spiperone, showed a typical competitive inhibition pattern when both the agonist and antagonist were applied simultaneously. Contrary to this, an insurmountable diminishing of the maximal cell response to serotonin was observed when the cells were preincubated with spiperone. We conclude that a combination of the coadministration and preincubation experimental setups is necessary for appropriate mechanistic interpretation and quantitative assessment of the antagonist activity when using transient functional readouts.
24
McGrath, P. A., J. R. Bourke, G. J. Huxham, and S. W. Manley. "Electrical responses of cultured porcine thyroid cells to adrenergic agents." Journal of Endocrinology 107, no. 1 (October 1985): 23–30. http://dx.doi.org/10.1677/joe.0.1070023.
Full textAbstract:
ABSTRACT The membrane potential of cultured porcine thyroid follicular cells depolarized by up to 20 mV from the resting value of about − 73 mV on exposure to β-adrenoceptor agonists. A similar response was induced by TSH or dibutyryl cyclic AMP. α-Adrenoceptor agonists were without effect. The receptor subtype was shown to be (at least predominantly) β2 by the order of potency for β-agonists (isoprenaline ≅ fenoterol⪢adrenaline >noradrenaline) and by the relative potency of selective β-antagonists (ICI 118,551 ⪢atenolol). The α-agonist phenylephrine had no effect on the TSH response but weakly inhibited the β-agonist response. Rather than a physiological antagonism between α- and β-adrenoceptor-mediated responses, this effect was shown to be due to the weak β-antagonist effect of phenylephrine since the α-antagonist phentolamine failed to potentiate the depolarizing response to the mixed agonist nor-adrenaline, and also failed to block the inhibitory action of phenylephrine on the β-agonist effect. Sensitivity to β-agonist was enhanced by omission of serum from the culture medium and reduced by exposure to β-agonists or a high concentration of TSH or dibutyryl cyclic AMP. J. Endocr. (1985) 107, 23–30
25
Keele, N. Bradley, Volker Neugebauer, and Patricia Shinnick-Gallagher. "Differential Effects of Metabotropic Glutamate Receptor Antagonists on Bursting Activity in the Amygdala." Journal of Neurophysiology 81, no. 5 (May 1, 1999): 2056–65. http://dx.doi.org/10.1152/jn.1999.81.5.2056.
Full textAbstract:
Differential effects of metabotropic glutamate receptor antagonists on bursting activity in the amygdala. Metabotropic glutamate receptors (mGluRs) are implicated in both the activation and inhibition of epileptiform bursting activity in seizure models. We examined the role of mGluR agonists and antagonists on bursting in vitro with whole cell recordings from neurons in the basolateral amygdala (BLA) of amygdala-kindled rats. The broad-spectrum mGluR agonist 1 S,3 R-1-aminocyclopentane dicarboxylate (1 S,3 R-ACPD, 100 μM) and the group I mGluR agonist ( S)-3,5-dihydroxyphenylglycine (DHPG, 20 μM) evoked bursting in BLA neurons from amygdala-kindled rats but not in control neurons. Neither the group II agonist (2 S,3 S,4 S)-α-(carboxycyclopropyl)-glycine (l-CCG-I, 10 μM) nor the group III agonistl-2-amino-4-phosphonobutyrate (l-AP4, 100 μM) evoked bursting. The agonist-induced bursting was inhibited by the mGluR1 antagonists (+)-α-methyl-4-carboxyphenylglycine [(+)-MCPG, 500 μM] and ( S)-4-carboxy-3-hydroxyphenylglycine [( S)-4C3HPG, 300 μM]. Kindling enhanced synaptic strength from the lateral amygdala (LA) to the BLA, resulting in synaptically driven bursts at low stimulus intensity. Bursting was abolished by (S)-4C3HPG. Further increasing stimulus intensity in the presence of ( S)-4C3HPG (300 μM) evoked action potential firing similar to control neurons but did not induce epileptiform bursting. In kindled rats, the same threshold stimulation that evoked epileptiform bursting in the absence of drugs elicited excitatory postsynaptic potentials in ( S)-4C3HPG. In contrast (+)-MCPG had no effect on afferent-evoked bursting in kindled neurons. Because (+)-MCPG is a mGluR2 antagonist, whereas ( S)-4C3HPG is a mGluR2 agonist, the different effects of these compounds suggest that mGluR2 activation decreases excitability. Together these data suggest that group I mGluRs may facilitate and group II mGluRs may attenuate epileptiform bursting observed in kindled rats. The mixed agonist–antagonist ( S)-4C3HPG restored synaptic transmission to control levels at the LA-BLA synapse in kindled animals. The different actions of ( S)-4C3HPG and (+)-MCPG on LA-evoked bursting suggests that the mGluR1 antagonist–mGluR2 agonist properties may be the distinctive pharmacology necessary for future anticonvulsant compounds.
26
Zhang, Xun, M. Jeyakumar, Sergei Petukhov, and Milan K. Bagchi. "A Nuclear Receptor Corepressor Modulates Transcriptional Activity of Antagonist-Occupied Steroid Hormone Receptor." Molecular Endocrinology 12, no. 4 (April 1, 1998): 513–24. http://dx.doi.org/10.1210/mend.12.4.0089.
Full textAbstract:
Abstract Synthetic steroid hormone antagonists are clinically important compounds that regulate physiological responses to steroid hormones. The antagonists bind to the hormone receptors, which are ligand-inducible transcription factors, and modulate their gene-regulatory activities. In most instances, a steroid receptor, such as progesterone receptor (PR) or estrogen receptor (ER), is transcriptionally inactive when complexed with an antagonist and competitively inhibits transactivation of a target steroid-responsive gene by the cognate hormone-occupied receptor. In certain cellular and promoter contexts, however, antagonist-occupied PR or ER acquires paradoxical agonist-like activity. The cellular mechanisms that determine the switch from the negative to the positive mode of transcriptional regulation by an antagonist-bound steroid receptor are unknown. We now provide strong evidence supporting the existence of a cellular inhibitory cofactor that interacts with the B form of human PR (PR-B) complexed with the antiprogestin RU486 to maintain it in a transcriptionally inactive state. In the presence of unliganded thyroid hormone receptor (TR) or ER complexed with the antiestrogen 4-hydroxytamoxifen, which presumably sequesters a limiting pool of the inhibitory cofactor, RU486-PR-B functions as a transcriptional activator of a progesterone-responsive gene even in the absence of hormone agonist. In contrast, hormone-occupied TR or ER fails to induce transactivation by RU486-PR-B. Recent studies revealed that a transcriptional corepressor, NCoR (nuclear receptor corepressor), interacts with unliganded TR but not with liganded TR. Interestingly, coexpression of NCoR efficiently suppresses the partial agonistic activity of antagonist-occupied PR-B but fails to affect transactivation by agonist-bound PR-B. We further demonstrate that RU486-PR-B interacts physically with NCoR in vitro. These novel observations suggest that the inhibitory cofactor that associates with RU486-PR-B and represses its transcriptional activity is either identical or structurally related to the corepressor NCoR. We propose that cellular mechanisms that determine the switch from the antagonistic to the agonistic activity of RU486-PR-B involve removal of the corepressor from the antagonist-bound receptor so that it can effect partial but significant gene activation.
27
Sheikh-Hamad, D., Y. P. Wang, O. D. Jo, and N. Yanagawa. "Dopamine antagonizes the actions of angiotensin II in renal brush-border membrane." American Journal of Physiology-Renal Physiology 264, no. 4 (April 1, 1993): F737—F743. http://dx.doi.org/10.1152/ajprenal.1993.264.4.f737.
Full textAbstract:
In the present study, we examined the effects of dopamine and angiotensin II (ANG II) in renal brush-border membrane (BBM). With isolated BBM vesicles, dopamine (> 10(-4) M) directly inhibited BBM 22Na+ uptake and activated phospholipase C (PLC). These effects were mimicked by DA1 agonist but not DA2 agonist and were prevented by DA1 antagonist but not DA2 antagonist, indicating the involvement of DA1 receptors. In contrast to dopamine, ANG II directly stimulated BBM 22Na+ uptake and activated BBM phospholipase A2 (PLA2). Neither dopamine nor ANG II altered BBM adenosine 3',5'-cyclic monophosphate content. In the presence of dopamine, ANG II failed to stimulate BBM Na+ uptake and PLA2. However, both DA1 and DA2 agonists similarly abrogated the actions of ANG II, and both DA1 and DA2 antagonists were required to restore ANG II actions in the presence of dopamine, indicating the involvement of both DA1 and DA2 receptors in the antagonistic effect of dopamine. Dopamine, as well as DA1 or DA2 agonists, also lowered 125I-ANG II BBM binding. In summary, these results show that, in renal BBM, dopamine impedes ANG II receptor binding and antagonizes the stimulatory effects of ANG II on Na+ uptake and PLA2. This occurred through both DA1 and DA2 receptors and independent of DA1 effects on BBM Na+ uptake or PLC.
28
Quan, N., L. Xin, A. L. Ungar, and C. M. Blatteis. "Preoptic norepinephrine-induced hypothermia is mediated by alpha 2-adrenoceptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 262, no. 3 (March 1, 1992): R407—R411. http://dx.doi.org/10.1152/ajpregu.1992.262.3.r407.
Full textAbstract:
We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area of conscious guinea pigs evokes a fall in core temperature (Tco) that is mediated by a reduction in metabolic rate. To identify the adrenoceptor subtype(s) involved in this effect, we microdialyzed intrapreoptically various adrenergic agonists or antagonists singly or in combinations. Tco and ear skin temperatures of the animals were monitored throughout the experiments. alpha 1-, beta-, beta 1-, and beta 2-agonists and antagonists did not induce significant Tco changes. Although the alpha 2-antagonists yohimbine (Yoh) and rauwolscine (Rau) did not have thermal effects per se, the alpha 2-agonist clonidine evoked dose-dependent Tco falls that were abolished by codialyzed Yoh and Rau. The microdialysis of NE evoked, as before, a 0.7 +/- 0.2 degrees C Tco fall; it was abolished by the codialyzed alpha-antagonist phentolamine, Yoh, and Rau but not by the beta-antagonist propranolol. No adrenoceptor agonist induced changes in ear skin temperature. These results indicate that the hypothermizing effect of intrapreoptically microdialyzed NE is achieved by a reduction in metabolic heat production, mediated by alpha 2-adrenoceptors.
29
Nikolaus, Susanne, Markus Beu, Hans-Jörg Wittsack, Anja Müller-Lutz, Christina Antke, Hubertus Hautzel, Yuriko Mori, Eduards Mamlins, Gerald Antoch, and Hans-Wilhelm Müller. "GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat." Reviews in the Neurosciences 31, no. 6 (August 27, 2020): 569–88. http://dx.doi.org/10.1515/revneuro-2019-0112.
Full textAbstract:
AbstractIn this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.
30
Varma, Daya R. "Ligand-independent negative chronotropic responses of rat and mouse right atria to β-adrenoceptor antagonists." Canadian Journal of Physiology and Pharmacology 77, no. 12 (November 15, 1999): 943–49. http://dx.doi.org/10.1139/y99-099.
Full textAbstract:
Negative chronotropic effects of β-adrenoceptor (βAR) antagonists on right atria from reserpine-treated rats and mice were determined as a test of their inverse agonist activities. β2AR antagonist ICI-118,551 and nonselective βAR antagonists alprenolol, propranolol, and timolol produced negative chronotropic effects. In contrast, nonselective βAR antagonists pindolol and nadolol as well as β1AR-selective antagonists atenolol, acebutolol, and metoprolol did not cause a significant decrease in atrial rates. The neutral antagonist pindolol but not the inverse agonist alprenolol inhibited the negative chronotropic activities of ICI-118,551. Isoprenaline, salbutamol, and noradrenaline produced positive chronotropic effects; the chronotropic effects of isoprenaline and salbutamol but not of noradrenaline were antagonized by ICI-118,551. It is concluded that both β1AR and β2AR mediate positive chronotropic effects of catecholamines on rat and mouse atria but only β2AR are constitutively active.Key words: inverse agonism, ICI-118,551, β1 adrenoceptor-selective antagonists, chronotropic responses, catecholamines.
31
Reis e Sousa, C., E. H. Levine, and R. N. Germain. "Partial signaling by CD8+ T cells in response to antagonist ligands." Journal of Experimental Medicine 184, no. 1 (July 1, 1996): 149–57. http://dx.doi.org/10.1084/jem.184.1.149.
Full textAbstract:
Structural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8+ T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern of early TCR-associated tyrosine phosphorylation events in CD4+ T cells. We have therefore directly examined proximal TCR signaling in a CD8+ T cell line in response to various related ligands. TCR engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR-associated tyrosine phosphorylation events as seen with CD4+ cells, including accumulation of both the p21 and p23 forms of phosphorylated zeta, phosphorylation of CD3 epsilon, and association of phosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, gamma interferon secretion, interleukin-2 receptor alpha upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta without net phosphorylation of CD3 epsilon, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR-dependent phosphorylation events in CD8+ T cells as first observed in CD4+ cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellular biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes.
32
Fujinoki, Masakatsu. "Melatonin-enhanced hyperactivation of hamster sperm." REPRODUCTION 136, no. 5 (November 2008): 533–41. http://dx.doi.org/10.1530/rep-08-0202.
Full textAbstract:
The effects of melatonin on reproductive function were examined using hamster spermatozoa. When 1 pM to 1 μM melatonin was added to the mTALP medium, hyperactivation was significantly enhanced. Antagonists and agonists of the melatonin receptor (i.e., MT1 and MT2) were added to the medium. Luzindole, an MT1 and MT2 competitive antagonist, significantly inhibited melatonin-induced hyperactivation, whereas the MT2-specific antagonists, 4-phenyl-2-propionamidotetralin andN-pentanoyl-2-benzyltryptamine, had no effect. Moreover, hyperactivation was significantly enhanced when non-specific agonists, such as 6-chloromelatonin and 2-iodomelatonin, were added to the medium. 8-Methoxy-2-propionamidotetralin, which is a strong MT2 agonist and a weak MT1 agonist, significantly increased hyperactivation, although the effect was weak. Therefore, it is likely that melatonin enhances sperm hyperactivation via the MT1 receptor.
33
Marceau, François, and Hélène Bachelard. "A Robust Bioassay of the Human Bradykinin B2 Receptor That Extends Molecular and Cellular Studies: The Isolated Umbilical Vein." Pharmaceuticals 14, no. 3 (February 24, 2021): 177. http://dx.doi.org/10.3390/ph14030177.
Full textAbstract:
Bradykinin (BK) has various physiological and pathological roles. Medicinal chemistry efforts targeted toward the widely expressed BK B2 receptor (B2R), a G-protein-coupled receptor, were primarily aimed at developing antagonists. The only B2R antagonist in clinical use is the peptide icatibant, approved to abort attacks of hereditary angioedema. However, the anti-inflammatory applications of B2R antagonists are potentially wider. Furthermore, the B2R antagonists notoriously exhibit species-specific pharmacological profiles. Classical smooth muscle contractility assays are exploited over a time scale of several hours and support determining potency, competitiveness, residual agonist activity, specificity, and reversibility of pharmacological agents. The contractility assay based on the isolated human umbilical vein, expressing B2R at physiological density, was introduced when investigating the first non-peptide B2R antagonist (WIN 64338). Small ligand molecules characterized using the assay include the exquisitely potent competitive antagonist, Pharvaris Compound 3 or the partial agonist Fujisawa Compound 47a. The umbilical vein assay is also useful to verify pharmacologic properties of special peptide B2R ligands, such as the carboxypeptidase-activated latent agonists and fluorescent probes. Furthermore, the proposed agonist effect of tissue kallikrein on the B2R has been disproved using the vein. This assay stands in between cellular and molecular pharmacology and in vivo studies.
34
Cone, Eugene Blanchard, Maya Marchese, Stephen Reese, Junaid Nabi, Kerry L. Kilbridge, and Quoc-Dien Trinh. "Lower odds of cardiac events for gonadotropic releasing hormone antagonists versus agonists." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 34. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.34.
Full textAbstract:
34 Background: Gonadotropic releasing hormone (GnRH) agonists and antagonists are first-line for advanced prostate cancer, but may be associated with cardiac toxicity. Observational studies show a relatively lower risk for GnRH antagonists, but a randomized trial found no difference. We compared the reporting of cardiac events for GnRH agonists and antagonists. Methods: We used VigiBase, the World Health Organization global database of case safety reports, which collects data from more than 130 countries to extract drug-adverse event (AE) pairs. Using Medical Dictionary for Regulatory Activities terminology, we identified AEs related to GnRH antagonist (degarelix) or agonist (leuprolide, goserelin, triptorelin, histrelin) therapy for prostate cancer, including myocardial infarction, heart failure, cardiomyopathies, new-onset valvular dysfunction, and other major cardiac events. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected. Results: We found 10,504 AEs for GnRH agonists, and 1,606 for GnRH antagonists; 805 (7.7%) were cardiac for agonists, and 102 for antagonists (6.4%). We found no signal for overall cardiac events or any subgrouping for GnRH antagonists, but identified a signal both for overall cardiac events (ROR 1.20, 95% CI 1.12-1.29) and myocardial infarction (1.76, 1.57-1.97) for GnRH agonists. Conclusions: Using validated pharmacovigilance methodology, we found a signal for myocardial infarction for GnRH agonists, but did not detect one for GnRH antagonists. As cardiovascular disease is the most common cause of non-cancer death in prostate cancer patients, this finding is of specific relevance in the current era of novel second-line anti-androgen therapies which may compound toxicity when added to first-line therapy. The relative cardiac toxicity of GnRH agonist therapy compared to GnRH antagonists merits renewed attention.
35
Wolska, Nina, Hassan Kassassir, Boguslawa Luzak, Cezary Watala, and Marcin Rozalski. "Adenosine Receptor Agonists Increase the Inhibition of Platelet Function by P2Y12 Antagonists in a cAMP- and Calcium-Dependent Manner." Pharmaceuticals 13, no. 8 (July 31, 2020): 177. http://dx.doi.org/10.3390/ph13080177.
Full textAbstract:
We have shown previously that platelet activity can be lowered through the simultaneous inhibition of P2Y12 receptor and activation of adenosine receptors (AR). This work explores this concept by testing the antiplatelet potential of nine AR agonists in combination with P2Y12 receptor antagonists—cangrelor and prasugrel metabolite. A panel of in vitro methods was used to assess platelet viability, P-selectin expression, GPIIb-IIIa activation, fibrinogen binding, calcium ion mobilization, VASP-P level, and cAMP formation, utilizing whole blood or isolated platelets from healthy volunteers. The AR agonists demonstrated anti-platelet effects, but stimulated signaling pathways to varying degrees. AR agonists and P2Y12 antagonists reduced expression of both P-selectin and the activated form of GPIIb-IIIa on platelets; however, the combined systems (AR agonist + P2Y12 antagonist) demonstrated stronger effects. The antiplatelet effects of AR when combined with P2Y12 were more pronounced with regard to exogenous fibrinogen binding and calcium mobilization. The cAMP levels in both resting and ADPactivated platelets were increased by AR agonist treatment, and more so when combined with P2Y12 inhibitor. In conclusion, as AR agonists are fast-acting compounds, the methods detecting early activation events are more suitable for assessing their antiplatelet action. The exogenous fibrinogen binding, calcium mobilisation and cAMP level turned out to be sensitive markers for detecting the inhibition caused by AR agonists alone or in combination with P2Y12 receptor antagonists.
36
Danielsson, Jennifer, Aisha S. Kuforiji, Gene T. Yocum, Yi Zhang, Dingbang Xu, George Gallos, and Charles W. Emala. "Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 2 (February 1, 2020): L287—L295. http://dx.doi.org/10.1152/ajplung.00552.2018.
Full textAbstract:
TMEM16A (anoctamin 1) is an important calcium-activated chloride channel in airway smooth muscle (ASM). We have previously shown that TMEM16A antagonists such as benzbromarone relax ASM and have proposed TMEM16A antagonists as novel therapies for asthma treatment. However, TMEM16A is also expressed on airway epithelium, and TMEM16A agonists are being investigated as novel therapies for cystic fibrosis. There are theoretical concerns that agonism of TMEM16A on ASM could lead to bronchospasm, making them detrimental as airway therapeutics. The TMEM16A agonist Eact induced a significant contraction of human ASM and guinea pig tracheal rings in an ex vivo organ bath model. Pretreatment with two different TMEM16A antagonists, benzbromarone or T16Ainh-A01, completely attenuated these Eact-induced contractions. Pretreatment with Eact alone augmented the maximum acetylcholine contraction. Pretreatment of A/J mice in vivo with nebulized Eact caused an augmentation of methacholine-induced increases in airway resistance measured by the forced oscillatory technique (flexiVent). Pretreatment with the TMEM16A antagonist benzbromarone significantly attenuated methacholine-induced increases in airway resistance. In in vitro cellular studies, TMEM16A was found to be expressed more abundantly in ASM compared with epithelial cells in culture (8-fold higher in ASM). Eact caused an increase in intracellular calcium in human ASM cells that was completely attenuated by pretreatment with benzbromarone. Eact acutely depolarized the plasma membrane potential of ASM cells, which was attenuated by benzbromarone or nifedipine. The TMEM16A agonist Eact modulates ASM contraction in both ex vivo and in vivo models, suggesting that agonism of TMEM16A may lead to clinically relevant bronchospasm.
37
Homer, L. D., and T. B. Nielsen. "Spare receptors, partial agonists, and ternary complex model of drug action." American Journal of Physiology-Endocrinology and Metabolism 253, no. 1 (July 1, 1987): E114—E121. http://dx.doi.org/10.1152/ajpendo.1987.253.1.e114.
Full textAbstract:
The occurrence of spare receptors and partial agonists for smooth muscle contractions mediated by alpha 1-adrenergic receptors can be accounted for with a ternary complex model of drug action presented here. In this model, receptor-ligand complexes are assumed to be inactive until the complex binds to an activating protein. Contractile responses are assumed to be proportional to the concentration of ternary complex (receptor-ligand-activator) regardless of the ligand involved. Antagonists are unable to form the ternary complex. Spare receptors are present as the inactive receptor-ligand complex. Such a model is shown to fit already published data on membrane binding of alpha 1-adrenergic agonists as well as contractile responses to the agonist. Schild plots are expected to resemble those of a single-site model of drug action. The double-reciprocal plots of receptor-inactivation studies will display only a slight curvature as may be seen in previously published articles. Partial agonists may have 50% response doses lowe or higher than full agonists. The hypothesis that ternary complexes are formed with alpha 1-receptors could be tested more critically with receptor-inactivation studies using both antagonists and agonists. Partial inactivation of receptor and activator protein should reduce the binding of antagonist without altering the concentration needed to bind to 50% of the receptors. On the other hand, the concentration of agonist required to displace 50% of a bound antagonist is expected to increase. The proposal that contractile responses are proportional to the ternary complex concentration could be tested by fitting the ternary complex model to the data from studies of contractions induced by partial agonists as well as full agonists.
38
Labudda, Olga, Tomasz Wierzba, Dariusz Sobolewski, Małgorzata Sleszyńska, Łukasz Gawiński, Marketa Plackova, Jirina Slaninová, and Adam Prahl. "New bradykinin analogues acylated on the N-terminus: effect on rat uterus and blood pressure." Acta Biochimica Polonica 54, no. 1 (January 9, 2007): 193–98. http://dx.doi.org/10.18388/abp.2007_3286.
Full textAbstract:
Our previous studies suggested that acylation of the N-terminus of several known B2 antagonists with various kinds of bulky acyl groups consistently improved their antagonistic potency in rat blood pressure assay. On the other hand, our earlier observations also seemed to suggest that the effects of acylation on the contractility of isolated rat uterus depended substantially on the chemical character of the acyl group, as we observed that this modification might either change the range of antagonism or even transform it into agonism. Bearing all this in mind, we decided to synthesize seven new analogues of bradykinin by N-terminal acylation with various acyl groups of a moderately potent B2 antagonist, previously synthesized by Stewart's group, D-Arg-Arg-Pro-Hyp-Gly-Thr-Ser-D-Phe-Thi-Arg. The analogues were tested in vitro for their blood pressure-lowering and uterotonic activities. The modifications either preserved or increased the antagonistic potency in the rat blood pressure test. On the other hand, all seven substituents negatively influenced the interaction with the rat uterine receptors. Our results may be helpful for designing new B2 agonists and antagonists.
39
Brooks, D. P., L. Share, and J. T. Crofton. "Central adrenergic mechanisms in hemorrhage-induced vasopressin secretion." American Journal of Physiology-Heart and Circulatory Physiology 251, no. 6 (December 1, 1986): H1158—H1162. http://dx.doi.org/10.1152/ajpheart.1986.251.6.h1158.
Full textAbstract:
The effect of central administration of specific adrenergic agonists and antagonists on hemorrhage-induced vasopressin secretion was studied in conscious rats. The intracerebroventricular (icv) injection of the alpha 2-antagonist yohimbine, the alpha 1-antagonist corynanthine, or the beta-agonist isoproterenol failed to alter the vasopressin or blood pressure responses to two sequential 10% reductions in blood volume. Administration of the beta-antagonist propranolol, however, resulted in a significant attenuation of the vasopressin response to hemorrhage, with little effect on the blood pressure response. The alpha 2-agonist, butylated hydroxytoluene (BHT) 933, caused an enhanced vasopressin response to hemorrhage, with a resulting improved maintenance in blood pressure. The results indicate that both alpha 2- and beta-adrenoreceptors may be involved in the pressure-volume control of vasopressin secretion.
40
Rattan, S., and R. Shah. "Influence of purinoceptors' agonists and antagonists on opossum internal anal sphincter." American Journal of Physiology-Gastrointestinal and Liver Physiology 255, no. 3 (September 1, 1988): G389—G394. http://dx.doi.org/10.1152/ajpgi.1988.255.3.g389.
Full textAbstract:
Studies were performed in alpha-chloralose-anesthetized and pancuronium-treated opossums. Resting internal anal sphincter pressures (IASP) were monitored using low-compliant continuously perfused catheters. P1 and P2 purinoceptor agonists, adenosine and ATP, respectively, administered close intra-arterially, caused dose-dependent decreases in the IASP. The inhibitory effect of these agonists on the IASP was tetrodotoxin resistant. Rectal balloon distension (RD) (which mimics the rectoanal inhibitory reflex) caused volume-dependent IAS relaxation. Electrical stimulation of the sacral nerve (SNS) also produced frequency-dependent decreases in IASP. The inhibitory response to adenosine (P1 purinoceptor agonist), ATP (P2 purinoceptor agonist), RD, and SNS on the internal anal sphincter (IAS) was examined before and after 8-phenyltheophylline (P1 purinoceptor antagonist) and alpha,beta-methylene ATP (P2 purinoceptor antagonist that irreversibly binds and desensitizes P2 purinoceptor). P1 and P2 purinoceptor antagonists produced selective antagonism of the inhibitory responses on the IAS of their respective agonists only. Furthermore, high doses of adenosine and ATP produced desensitization and block of their own actions only. The purinoceptors' antagonists, and the desensitization of purinoceptors by high doses of adenosine and ATP, failed to modify the fall in IASP in response to RD or SNS. From these studies we conclude that distinct inhibitory P1 and P2 purinoceptors are present on the IAS smooth muscle. However, these inhibitory purinoceptors may not be responsible for the rectoanal reflex-mediated IAS relaxation.
41
Waelbroeck, M., P. Robberecht, P. Chatelain, P. de Neef, and J. Christophe. "Effects of temperature and ethanol on agonist and antagonist binding to rat heart muscarinic receptors in the absence and presence of GTP." Biochemical Journal 231, no. 2 (October 15, 1985): 469–76. http://dx.doi.org/10.1042/bj2310469.
Full textAbstract:
The effect of temperature on the binding of four agonists and three antagonists to rat heart muscarinic receptors was studied in the absence and presence of GTP. The binding of agonists to two states (or classes) of receptors, in the absence of GTP, led to enthalpy and entropy changes that decreased sharply above 25 degrees C, suggesting that agonists induced ‘isomerization’ reactions (large conformational changes and/or receptor-effector association). Both temperature increase and ethanol decreased hydrophobic interactions, thereby hindering binding and/or agonist-induced ‘isomerization’ reactions. Addition of GTP to the incubation medium also appeared to reverse (or prevent) ‘isomerization’ reactions. For agonist binding to the low-affinity state, in the presence of GTP, and for antagonist binding, the thermodynamic parameters observed could be readily explained by simple receptor-ligand associations; large entropy increases and small enthalpy increases, provoked by hydrophobic and ionic interactions, were partly neutralized by entropy and enthalpy decreases, due to hydrogen bonds and van der Waals interactions. The muscarinic antagonists used (atropine, n-methylscopolamine and dexetimide), being more hydrophobic molecules than the agonists tested (carbamylcholine, oxotremorine and pilocarpine), induced larger entropy changes or more negative enthalpy changes.
42
Margel, David, Avivit Peer, Yaara Ber, Sivan Sela, Liat Shavit Grievink, Tzlil Tabachnik, Guy Witberg, et al. "Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5015. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5015.
Full textAbstract:
5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.
43
Bonaventura, Jordi, Gemma Navarro, Verònica Casadó-Anguera, Karima Azdad, William Rea, Estefanía Moreno, Marc Brugarolas, et al. "Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer." Proceedings of the National Academy of Sciences 112, no. 27 (June 22, 2015): E3609—E3618. http://dx.doi.org/10.1073/pnas.1507704112.
Full textAbstract:
Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.
44
Sairam, M. R., J. Linggen, J. Sairam, and G. N. Bhargavi. "Influence of carbohydrates on the antigenic structure of gonadotropins: distinction of agonists and antagonists." Biochemistry and Cell Biology 68, no. 5 (May 1, 1990): 889–93. http://dx.doi.org/10.1139/o90-131.
Full textAbstract:
The biological properties of glycosylated (native) and deglycosylated gonadotropins are different. The immunological characteristics of antibodies prepared against deglycosylated lutropin and human chorionic gonadotropin were investigated. Distinct antibodies of rabbit polyclonal antisera against deglycosylated lutropin and deglycosylated chorionic gonadotropin were separated by affinity chromatography on divinylsulfonyl-Sepharose-immobilized hormone or antagonist columns, respectively, in successive runs. Antibodies that could discriminate between agonist and antagonistic forms of the hormones could thus be obtained. In radioimmunoassays using 125I-labeled antagonists and respective antagonist antibodies, only the deglycosylated hormones or their deglycosylated α-subunits showed preferential reaction. Based on recombinations using different deglycosylated subunits, it was concluded that the loss of antennary sugars in the α-subunits was mainly responsible for the changes that led to the formation of antagonist-specific antibodies. Only the agonist-specific antibody could neutralize hormone action. Thus, the type and extent of glycosylation appears to influence the antigenic structure of these secreted glycoproteins.Key words: gonadotropins, glycoproteins, antigenic structure, affinity chromatography, agonist, antagonist.
45
Vilhardt, H., and S. Lundin. "Antidiuretic antagonism and agonism of 1-deamino-pentamethylene-2-d-phenylalanine-4-isoleucine-arginine vasopressin in rats with diabetes insipidus." Journal of Endocrinology 112, no. 3 (March 1987): 439–42. http://dx.doi.org/10.1677/joe.0.1120439.
Full textAbstract:
ABSTRACT Using implanted minipumps it was shown over a period of 7 days that the vasopressin antagonist, 1-deamino-pentamethylene-2-d-Phe-4-Ile-arginine vasopressin, caused increased diuresis in normal rats and reversed vasopressin- or oxytocin-induced antidiuresis in Brattleboro rats. When the antagonist was infused alone in Brattleboro rats it induced a marked antidiuretic response, indicating that the analogue also possessed agonistic properties. The agonist action could not be demonstrated in anaesthetized, hydrated normal rats. In these animals the analogue behaved as a pure antagonist. It is concluded that analogues which behave as antagonists in one test model may display agonistic properties under different experimental conditions. J. Endocr. (1987) 112, 439–442
46
Ajit, Seena K., Mark H. Pausch, Jeffrey D. Kennedy, and Edward J. Kaftan. "Development of a FLIPR Assay for the Simultaneous Identification of MrgD Agonists and Antagonists from a Single Screen." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/326020.
Full textAbstract:
MrgD, a member of the Mas-related gene family, is expressed exclusively in small diameter neurons in the dorsal root ganglion. This unique expression pattern, the presence of a single copy of MrgD in rodents and humans, and the identification of a putative ligand, beta-alanine, make it an experimentally attractive therapeutic target for pain with limited likelihood of side effects. We have devised a high throughput calcium mobilization assay that enables identification of both agonists and antagonists from a single screen for MrgD. Screening of the Library of Pharmacologically Active Compounds (LOPAC) validated this assay approach, and we identified both agonists and antagonists active at micromolar concentrations in MrgD expressing but not in parental CHO-DUKX cell line. Further characterization was performed using a subset of these screening hits. Our results demonstrated that the dual agonist/antagonist assay format is feasible and likely can be extended to most GPCRs with known agonist.
47
Gurevich, Natasha, Peter H. Wu, and Peter L. Carlen. "Serotonin agonist and antagonist actions in hippocampal CA1 neurons." Canadian Journal of Physiology and Pharmacology 68, no. 5 (May 1, 1990): 586–95. http://dx.doi.org/10.1139/y90-085.
Full textAbstract:
The actions of serotonin (5-HT) and its putative agonists and antagonists were examined in vitro on hippocampal CA1 neurons using intracellular recordings, demonstrating that the cellular pharmacological effects can not necessarily be predicted from binding characteristics alone. The first response following 5-HT application was often a long-lasting (several minutes) hyperpolarization associated with decreased input resistance. Subsequent 5-HT applications caused only brief hyperpolarizations (30–120 s) and associated decreased input resistance, often followed by membrane depolarization. The post-spike train afterhyperpolarization (AHP) was prolonged for several minutes following the 5-HT induced hyperpolarization. 5-HT1 agonists (8-hydroxy-2-(di-n-propylamino)tetralin, 5-methoxytryptamine, MK-212) caused a prolonged hyperpolarization, decreased input resistance, and enhancement of the AHP. 5-HT applied following agonist application elicited only short-lasting hyperpolarizations. The 5-HT2 antagonists, cyproheptadine and mianserin, and a nonspecific 5-HT antagonist, methysergide, also caused a prolonged hyperpolarization with decreased input resistance. Spiperone, a nonspecific 5-HT antagonist, and ritanserin, a putative specific 5-HT2 receptor antagonist, depolarized CA1 neurons with little or no change in input resistance. The 5-HT-induced short-lasting hyperpolarization was not affected by drop application of 5-HT antagonists, except for methysergide, but perfusion of methysergide, ritanserin, and spiperone attenuated this response. The long-lasting 5-HT hyperpolarization might be mediated by 5-HT1A receptor activation, and the short-lasting hyperpolarization by another serotonergic receptor subtype.Key words: 5-hydroxytryptamine agonists, 5-hydroxytryptamine antagonists, CA1 neurons, intracellular recording, rat hippocampus.
48
Menozzi, D., J. D. Gardner, R. T. Jensen, and P. N. Maton. "Properties of receptors for gastrin and CCK on gastric smooth muscle cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 257, no. 1 (July 1, 1989): G73—G79. http://dx.doi.org/10.1152/ajpgi.1989.257.1.g73.
Full textAbstract:
Previous studies have demonstrated that cholecystokinin (CCK), gastrin, and structurally related peptides can interact with various types of receptors that can be distinguished by their relative affinities for agonists and antagonists. In the present study we examined the effect of gastrin, the COOH-terminal octapeptide of CCK (CCK-8), and the tetrapeptide of CCK (CG-4) on contraction of dispersed gastric smooth muscle cells from guinea pig and tested the ability of various CCK receptor antagonists to affect agonist-induced muscle cell contraction. For purposes of comparison we tested the effect of each antagonist on CCK-stimulated amylase secretion by pancreatic acini from guinea pig. On gastric smooth muscle cells, CCK-8, gastrin, and CG-4 were all full agonists. CCK-8 and gastrin were equipotent and CG-4 was 6,000-fold less potent. Each antagonist caused inhibition of CCK-stimulated contraction with relative potencies (IC50): L364,718 (4 microM) = CBZ-CCK-(27-32)-NH2 (3 microM) greater than proglumide analogue 10 (90 microM). Inhibition by each of the antagonists was competitive in nature, specific for CCK peptides, and each had the same IC50 whether contraction was stimulated by CCK-8, gastrin, or CG-4. Relative potencies (IC50) of the three antagonists for inhibiting CCK-stimulated amylase release from pancreatic acini were L364,718 (3 nM) greater than proglumide analogue 10 (200 nM) greater than CBZ-CCK-(27-32)-NH2 (3 microM). These results demonstrate that gastric smooth muscle cells possess receptors that differ from CCK receptors on pancreatic acini in terms of affinities for both agonists and certain antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
49
Preckel, Tobias, Rudolf Grimm, Stefan Martin, and Hans Ulrich Weltzien. "Altered Hapten Ligands Antagonize Trinitrophenyl-specific Cytotoxic T Cells and Block Internalization of Hapten-specific Receptors." Journal of Experimental Medicine 185, no. 10 (May 19, 1997): 1803–13. http://dx.doi.org/10.1084/jem.185.10.1803.
Full textAbstract:
Low molecular chemicals (haptens) frequently cause T cell–mediated adverse immune reactions. Our previous work provided evidence that hapten-specific T cells, in analogy to those specific for nominal peptide antigens, direct their TCR towards hapten-modified, MHC-associated peptides. We now demonstrate that trinitrophenyl (TNP)-specific, class I MHC–restricted CTL from mice may exhibit exquisite specificity for subtle structural details of these hapten determinants, surpassing even the specificity of immunoglobulins. More importantly, these CTL could be antagonized by ligands altered either in their peptide sequence or in their hapten structure. The system was employed to examine the molecular basis of T cell antagonism. Whereas agonists resulted in a dose-dependent downregulation of TCR in different mouse T cell clones, antagonistic peptides totally failed to do so despite engaging the specific TCR. Moreover, simultaneous presentation of antagonist and agonist on the same antigen presenting cell prevented TCR internalization. No signs of anergy or functional receptor inactivation were observed in CTL treated with antagonist-loaded target cells. Based on a serial triggering model of T cell activation, our data favor a model in which antagonists block T cell functions by competitively engaging the specific TCR in unproductive interactions.
50
Elias, John J., Alfred F. Faust, Yung-Hua Chu, Edmund Y. Chao, and Andrew J. Cosgarea. "The Soleus Muscle Acts as an Agonist for the Anterior Cruciate Ligament: An in Vitro Experimental Study." American Journal of Sports Medicine 31, no. 2 (March 2003): 241–46. http://dx.doi.org/10.1177/03635465030310021401.
Full textAbstract:
Background: Although the quadriceps muscles are known antagonists for the anterior cruciate ligament and the hamstring muscles are known agonists, the influence of the calf muscles on knee stability is not well understood. Hypothesis: The soleus muscle acts as an anterior cruciate ligament agonist and the gastrocnemius muscle acts as an anterior cruciate ligament antagonist. Study Design: Controlled laboratory study. Methods: Six cadaveric knees were tested with individual and combined activation of the gastrocnemius and soleus muscles to determine the influence of simulated muscle contraction on tibiofemoral motion. Results: At all flexion angles, applying the soleus muscle force tended to translate the tibia posteriorly, whereas applying the gastrocnemius muscle force tended to translate the tibia anteriorly. Applying the soleus and gastrocnemius muscle forces together also tended to translate the tibia anteriorly. The average anterior and posterior tibial translations were greatest at 50° of flexion. Conclusions: The soleus muscle is capable of acting as an agonist for the anterior cruciate ligament and the gastrocnemius muscle can act as an antagonist. Clinical Relevance: A better understanding of the agonistic behavior of the soleus muscle on the anterior cruciate ligament may lead to the development of training and rehabilitation strategies that could reduce the incidence of injury and improve function in both patients with anterior cruciate ligament deficiency and patients who have undergone anterior cruciate ligament reconstruction.