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Horn, Johanna. "Calcium antagonists in stroke." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/58263.
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Paoletta, Silvia. "Designing adenosine receptors antagonists using an in silico approach." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422906.
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The neuromodulator adenosine affects a wide variety of physiopathological processes through activation of four receptors, classified as A1, A2A, A2B, and A3 subtypes. Adenosine receptors (ARs) belong to family A of G protein-coupled receptors (GPCRs) and are ubiquitously expressed in the human body. Activation or blockade of ARs is responsible for a wide range of effects in numerous organ systems; and therefore the regulation of ARs can have many potential therapeutic applications.
The main objective of this project has been the investigation of the in silico molecular pharmacology of adenosine receptors and, in particular, of the human A2A and A3 adenosine receptors to guide the discovery and the structural refinement of new potent and selective AR antagonists.
The recently published crystal structures of the human A2A adenosine receptor (hA2AAR) provide detailed three-dimensional information useful to support homology modeling studies and receptor-based drug design approaches. In particular, the 2.6 Å crystallographic structure of the hA2AAR in complex with the potent and selective antagonist ZM241385 was used as template to build a homology model of the hA3AR.
In order to validate the molecular docking protocols for the adenosine receptors family, the hA2AAR crystal structure was used to perform in parallel
molecular docking studies using different docking software. Then RMSD values between predicted and crystallographic poses of ZM241385 were calculated to select the docking protocol able to better reproduce this molecular system and to be used in the following molecular docking studies.
Subsequently, molecular docking studies of different ARs antagonists were performed at the hA3AR model and at the hA2AAR crystal structure, enabling the exploration of the potential effects of chemical modifications of these compounds, and thus facilitating the lead optimization process. Different series of new compounds belonging to known adenosine antagonists classes, including triazolo-triazines and pyrazolo-triazolo-pyrimidines, have been analyzed and modified with the aim to modulate their affinity towards different adenosine receptor subtypes, to increase their solubility, or to overcome their metabolic instability. Moreover, several compounds with simplified scaffolds have been proposed as new adenosine receptor antagonists; such as pyrazolo-pyrimidinones, phthalazinones and triazolo-pyrimidines.
Finally, the knowledge gained through the docking studies led to the identification of structural features of antagonist compounds important for the interaction with the hA3AR and was applied to the design of fluorescent ligands for this subtype, of particular interest as pharmacological probes.
In conclusion, the integration of in silico studies with synthetic work and pharmacological tests resulted to be a good strategy for the development of new compounds as adenosine receptors antagonists and led to a better understanding at the molecular level of this class of GPCRs.L’adenosina è un neuromodulatore che regola molti processi fisiopatologici attraverso l’attivazione di quattro diversi recettori accoppiati a proteine G (GPCRs), classificati come sottotipi A1, A2A, A2B e A3. I recettori adenosinici sono ubiquitari nell’organismo umano e la loro attivazione è responsabile di numerosi effetti in diversi organi. Proprio per questo motivo la regolazione dell’attività di questi recettori può avere interessanti applicazioni terapeutiche. Il principale obiettivo di questo progetto è stato l’analisi in silico a livello molecolare dei recettori adenosinici, ed in particolare dei recettori adenosinici umani A2A e A3, per guidare la scoperta e l’ottimizzazione strutturale di nuovi antagonisti adenosinici potenti e selettivi. Le strutture cristallografiche del recettore adenosinico umano A2A, recentemente pubblicate, forniscono dettagliate informazioni strutturali utili per supportare studi di homology modeling e approcci di drug design di tipo structure-based. In particolare, la struttura cristallografica del recettore adenosinico umano A2A, in complesso con l’antagonista potente e selettivo ZM241385, è stata utilizzata come templato per la costruzione di un modello per omologia del recettore adenosinico umano A3. Inoltre, con l’intento di selezionare il protocollo di docking molecolare più adatto per la famiglia dei recettori adenosinici, la struttura cristallografica del recettore adenosinico A2A è stata utilizzata per effettuare simulazioni di docking con diversi softwares in parallelo. Successivamente, le conformazioni ottenute dal docking sono state confrontate con la pose cristallografica di ZM241385 per selezionare il protocollo di docking che fosse in grado di riprodurre al meglio questo sistema molecolare e che potesse quindi essere usato per i successivi studi di docking. Sono stati quindi effettuati studi di docking molecolare di vari antagonisti adenosinici sul modello del recettore A3 e sulla struttura cristallografica del recettore A2A, in modo da ricavare informazioni che potessero facilitare il processo di ottimizzazione dei composti. Sono stati infatti analizzati numerosi nuovi composti appartenenti a classi note di antagonisti adenosinici, tra cui composti triazolotriazinici e tirazolotriazolopirimidinici, in modo da suggerire modifiche strutturali in grado di modularne l’affinità nei confronti dei vari sottotipi recettoriali adenosinici, di aumentarne la solubilità o di superarne i punti di instabilità metabolica. Diversi derivati con strutture semplificate, come per esempio composti pirazolopirimidinonici, ftalazinonici e triazolotriazinici, sono stati inoltre proposti come nuovi composti con attività antagonista nei confronti dei recettori adenosinici. Le informazioni ricavate grazie agli studi di docking hanno permesso l’identificazione di caratteristiche strutturali degli antagonisti adenosinici fondamentali per l’interazione con questi recettori. Queste informazioni sono state quindi applicate alla progettazione di derivati fluorescenti per il recettore adenosinico A3, che risultano particolarmente interessanti per il loro potenziale utilizzo in saggi farmacologici. In conclusione, quindi, questo studio sui recettori adenosinici dimostra come l’integrazione di metodologie computazionali con il lavoro sintetico e farmacologico risulta essere una strategia efficace per lo sviluppo di nuovi ligandi dei recettori adenosinici, a potenziale interesse terapeutico, e per il chiarimento di importanti aspetti strutturali riguardanti questa famiglia recettoriale e più in generale tutti i GPCRs.
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Lee, Hyosung. "DEVELOPMENT OF NOVEL AHR ANTAGONISTS." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/103.
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Aryl hydrocarbon receptor (AHR) is a sensor protein, activated by aromatic chemical species for transcriptionally regulating xenobiotic metabolizing enzymes. AHR is also known to be involved in a variety of pathogenesis such as cancer, diabetes mellitus, cirrhosis, asthma, etc. The AHR signaling induced by xenobiotics has been intensively studied whereas its physiological role in the absence of xenobiotics is poorly understood. Despite a number of ligands of AHR have been reported thus far, further applications are still hampered by the lack of specificity and/or the partially agonistic activity. Thus, a pure AHR antagonist is needed for deciphering the AHR cryptic as well as potential therapeutic agent. The Proteolysis Targeting Chimera (PROTAC) is a bi-functional small molecule containing a ligand and proteolysis inducer. PROTAC recruits the target protein to proteolysis machinery and elicits proteolysis. Thus far, a number of PROTAC have been prepared and demonstrated to effectively induce the degradation of targeted protein in cultured cells, validating PROTAC as a useful research tool. In the present study, PROTACs based on apigenin was prepared and demonstrated to induce the degradation of AHR, providing the proof of concept. To improve activity, a synthetic structure, CH-223191, was optimized for antagonistic activity by positional scanning identifying several AHR antagonists. PROTACs based on the optimal structure were prepared and assessed their biological activity. The products and synthetic scheme described hereby will be helpful for the further understanding on AHR biology as well as for developing therapeutic agents targeting AHR.
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Pasanisi, F. "Clinical pharmacology of calcium antagonists." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381477.
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McClean, Mercedes. "NMDA antagonists as antinociceptive agents." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311427.
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Abusara, Osama. "Neuropeptide antagonists for cancer treatment." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/neuropeptide-antagonists-for-cancer-treatment(e2f22b9f-f0a7-432d-89c4-7e65a2c71b69).html.
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Small Cell Lung Cancer (SCLC) is an aggressive form of cancer accounting for 25% of lung cancer deaths worldwide. Treatment relies on combination chemotherapy (etoposide and cisplatin or carboplatin) with or without radiation therapy. However, disease relapse and resistance occurs quickly, prompting unmet need for alternative treatment options. One such option is the use of broad-spectrum antagonists, known as Substance P (SP) analogues. Historically, these analogues have not succeeded clinically due to low potency and bioavailability. In this project, novel SP analogues were developed to address these shortfalls. A chemical strategy was designed to synthesise novel short peptides including DMePhe-DTrp-Phe-DTrp-Leu-NH2 (25) as the new lead. Fmoc and Boc D-Trp derivatives with indole nitrogen having substituents (methyl, ethyl, propyl, butyl, pentyl, propargyl, benzyl and tert-prenyl) were made and characterised by 1H and 13C NMR spectroscopy and mass spectrometry (MS). These building blocks were incorporated into the first series of peptides, substituting the D-Trp residue located near the C-terminal of 25, via solid and/or liquid phase procedures. Final products were purified by RP-HPLC to >90% purity and structures verified by MS and/or 1H NMR. Cell viability assays were conducted to evaluate cytotoxicity against two SCLC cell lines: H69 (chemo-naive) and DMS79 (from a patient after treatment). The IC50 values for the D-Trp residue modified peptides were < 5 μM. One of the earliest candidates to emerge from this work was DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu-NH2 (33). Subsequently, the most potent peptide was the one bearing D-Trp(N-butyl) (29) with IC50 values of 1.0 μM (H69) and 1.4 μM (DMS79), compared to the lead 25 with IC50 values of 30.7 μM (H69) and 23.0 μM (DMS79). A second series of peptides were produced to optimise 29 by incorporating a D-Trp(N-butyl) residue. The study focused on peptides by (a) modifying the N-terminal D-Trp residue, (b) modifying both D-Trp residues, (c) changing the C-terminal amide to free carboxylic acid, and (d) adding a charged amino acid (arginine) or removing a hydrophobic amino acid (leucine) to additionally aid in solubility. The most potent candidate was found to bear dual D-Trp(N-butyl) residues (35) with IC50 value of 0.6 μM (H69) and 2.3 μM (DMS79). Peptides 29 and 35 were at least 26 times more potent than SP antagonist G (SPG, previously subjected to a Phase I clinical trial), as revealed by in vitro screening in this project. Both sequences induced apoptosis as evident from fluorescence staining. Flow cytometric analysis of 29 with the DMS79 cell line showed that the level of late apoptotic cells rose from 36% at 2 μM to 96% at 6 μM, compared to 25 that exhibited no effect. Efficacy of peptide 33 was separately evaluated in vivo using DMS79 xenografts. A low dose (1.5 mg/kg) was found to reduce tumour growth by ~ 30% (p < 0.05) at day 7, relative to the control group. Higher doses could not be used due to limited aqueous solubility. Furthermore, these peptides were shown to have improved stability. Exposed to neat mouse plasma for 48 hours, 29 and 35 remained intact by 68.5% and 81.0%, respectively, compared to 59.0% for 25 and 35.9% for 33. Complete metabolic stability of 29 and 35 was observed after 3 hours incubation in mouse S9 liver fraction. Aqueous solubility issues were overcome in feasibility studies incorporating 29 into liposomes for future in vivo efficacy testing. Finally, due to the high potency and stability of 29, a liposomal formulation of it may have a profound effect in in vivo efficacy studies against chemo-resistant SCLC.
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Yocum, David. "Effective use of TNF antagonists." BioMed Central, 2004. http://hdl.handle.net/10150/610348.
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Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in disease progression or disability. With the emergence of structure-related outcome measures as the primary means for assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life. Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.
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Hughes, G. A. "Novel, potent antagonists of capsaicin." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445556/.
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The aim of this project was to explore and refine the conformational rationale for the activity of capsazepine (CPZ) as a blocker of the ion channel TRPV1 (transient receptor potential vanilloid type 1), by the synthesis and biological evaluation of further conformational constrained capsaicin analogues. The resolution of the stereoisomers of Af-(4-chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquino-line 29, Af-(4-chlorophenethylthio-carbamoyl)-6,7-dihydroxy-3-methyl-1,2,3,4-tetra-hydroisoquinoline 30 and N-(4-chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1,3-dimethyl-1,2,3,4-tetrahydroiso-quinoline 31 by stereoselective synthetic methodology is described, and some of the more unusual and interesting mechanisms are discussed. The novel asyrnmetric chemistry described includes the separation of the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by crystallisation with the enantiomers of mandelic acid, the use of sodium triacetoxyborohydride in the stereoselective reduction of 6,7-dimethoxy-l,3-dimethyl-3,4-dihydroiso-quinoline 171, to give the cw-diastereomers of 6,7-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 44, and the novel stereoselective route to the trans-diastereomers of 6,7-dimethoxy-l,3-dimethyl-l,2,3,4-tetrahydroisoquinoline 44 from the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by the Michael addition of A-benzyl-2-(3,4-dimethoxyphenyl)-l-methylethylamine 155 to ethynyl-4-tolylsulfone 150, followed by TFA-mediated cyclisation, single electron reductive desulfonylation and palladium-catalysed hydrogenolysis. The results of investigations into the conformational behaviour of the resolved stereoisomers of 29, 30 and 31 by techniques of NMR spectroscopy and molecular modelling, the evaluation of their biological activity at the rat and human orthologues of the ion channel TRPV1, and the attempted correlation of the two sets of data, with respect to the published conformational rationale for the activity of CPZ, are also described.
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Sozynski, Jan Maria. "Synthesis of Novel Ethylene Antagonists." Thesis, Curtin University, 2022. http://hdl.handle.net/20.500.11937/89600.
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In search of more user-friendly ethylene antagonists, synthesis of water soluble cycloproparenes and [1,2,3]triazolo[1,5-a]pyridines were targeted for this study. A series of precursors to water soluble cycloproparenes were synthesised, however all decomposed in the final reaction. Functionalised analogues of [1,2,3]triazolo[1,5-a]pyridines were prepared and demonstrated some anatgonism of ethylene action in a series of chemical reactivity and preliminary in vivo assays.
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Arthuso, Fernanda dos Santos. "Adaptação de células CHO secretoras de prolactina humana e seus antagonistas para o crescimento em suspensão." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-20062011-110202/.
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O Grupo de Hormônios do Centro de Biotecnologia do IPEN desenvolveu várias linhagens de células de ovário de hamster chinês (CHO) modificadas geneticamente e comprovadamente eficientes na expressão de proteínas heterólogas, dentre elas a prolactina humana (hPRL) e os análogos antagonistas de prolactina (S179D-hPRL e G129R-hPRL). No entanto, todas as linhagens para expressão são cultivadas em monocamadas e dependentes da presença de soro fetal bovino (SFB) no meio de cultivo para um crescimento eficiente. As células em suspensão apresentam um grande interesse industrial-farmacêutico, tanto pela facilidade de cultivo e ampliação de escala, como pela produtividade volumétrica. Desenvolvemos um protocolo para adaptação de células CHO para o crescimento em suspensão e também processos de produção em frascos spinners. Nesse trabalho foi realizada a adaptação das linhagens produtoras de hPRL; S179D-hPRL e G129R-hPRL para o crescimento em suspensão e em meio livre de SFB. Realizamos também a produção em escala laboratorial com as três linhagens adaptadas, assim como a correspondente purificação e caracterização de quatro proteínas heterólogas, incluindo a prolactina humana glicosilada (G-hPRL).The Hormone Group of the Biotechnology Center of IPEN has developed different cells lines of genetically modified chinese hamster ovary cells (CHO) for the expression of heterologus protein like human prolactin (hPRL) and its analogs/antagonists (S179D-hPRL and G129R-hPRL). All cell lines for expression are however cultured in monolayer culture dish and depend on fetal bovine serum (FBS) in the medium for an efficient growth. Cells in suspension show a great industrial-pharmaceutical interest, especially for the cultivation facility and scale enlargement as well as for volumetric productivity. We developed a protocol for adapting CHO cells to suspension growth, in spinner flasks. The adaption of our cell lines producing hPRL; S179D-hPRL and G129R-hPRL to suspension growth and in serum-free medium was obtained. We also carried out laboratory scale production with the three suspension-adapted culture line cells and the corresponding purification and characterization of four heterologous proteins, including glycosylated human prolactin (G-hPRL).
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Nobre, Rita Luisa Valentim de Avelar. "Viral interferon antagonists and antiviral drugs /." St Andrews, 2009. http://hdl.handle.net/10023/818.
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Goh, Wai Kean Chemistry Faculty of Science UNSW. "Novel antagonists of bacterial signaling pathways." Publisher:University of New South Wales. Chemistry, 2008. http://handle.unsw.edu.au/1959.4/41458.
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Traditional bacterial disease therapies utilize compounds that ultimately kill the target bacteria but it exerts a strong selective pressure on the bacteria to develop multi-drug resistance mutants. The increasing occurrence of resistance in common pathogens has highlighted the need to identify new anti-microbials that target the control of bacterial pathogenicity in a non-extermination manner to reduce the incidence of bacteria resistance. One new strategy exploits the discrete signaling molecules that regulate the various bacterial signaling pathways, which are responsible for the expression of pathogenicity traits. Halogenated furanones (fimbrolides) from the marine red alga, Delisea pulchra have been shown to interfere with the key signaling pathway present in Gram-negative bacteria by competitively displacing the cognate signaling molecule from the transcription protein. This project focused on the design and synthesis of 1,5-dihydropyrrol-2-ones, a new class of fimbrolide derivatives capable of displaying strong antagonistic properties of the fimbrolides. Primary synthetic methodologies examined include the halolactamization of allenamides and the direct lactone-lactam transformation. No doubt, both methodologies yielded the lactam ring, the former failed to introduce the crucial C-5 bromomethylene group essential for bioactivity. A facile high yielding two-step lactone-lactam transformation method was developed and using this method, a wide range of substituted 5-bromomethyl- and 5-dibromomethylene-1,5-dihydropyrrol-2-ones were synthesized. Furthermore, a new class of tricyclic crown-ether type compounds with no literature precedent were discovered. To vary the diversity of the compounds, a related class of compounds, 5,6-dihydroindol-2-ones, were examined. A general versatile method for the synthesis of 7-substituted 5,6-dihydroindol-2-ones was developed. The synthetic strategy proceeds via the established Suzuki-Miyaura cross-coupling reaction of halogenated dihydroindol-2-ones with arylboronic acids/esters. The Suzuki methodology was found to be reliable in furnishing a wide range of 7-substituted products in high yields. A preliminary molecular modeling approach was used to assist in the design of new anti-microbials via the ligand-docking analyses of the TraR and LasR protein. A positive correlation was observed between the docking scores and biological activity and the methodology was further developed into an initial screening tool to filter potential active and non-active compounds. The newly synthesized compounds were analysed for their efficacy in reducing the expression of the Green Fluorescent Protein (GFP) in the presence of natural AHL signaling molecules in an AHL-monitor strain, indicative of the inhibition of bacterial phenotype expression. The dihydropyrrol-2-one class of compounds showed significant biological activity and this highlighted their potential for further development.
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Gavalas, Nikolaos. "Lipid anchored truncated cytokine receptor antagonists." Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419273.
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Huckvale, R. "Photoactive antagonists for the GABAA receptor." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1475759/.
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GABAA receptors are an integral part of regulating neuronal transmission. Through the action of their endogenous agonist, γ-aminobutyric acid, they control most neuronal signal inhibition. GABAA receptors constantly move through the membrane, readily adapting to different stimuli, aided by transient interactions with scaffolding proteins. This thesis attempts to design and synthesise small, novel chemical tracking devices in order to gain insight into the driving forces of GABAA receptor diffusion. To this aim, photoaffinity labelled probe 1, based on a GABAA receptor antagonist gabazine, was synthesised. A benzophenone photoaffinity label was prepared, and installed onto a pyridazinyl-phenol core. A Sonogashira reaction, to install a carboxylic acid handle for the biotinylated linker, initially proved unsuccessful until the replacement of aryl bromide with an aryl iodide (Figure 1). Biotinylated probe 1 was associated with a quantum dot coated in streptavidin, and placed in live neurons. Real-time recording of the quantum dot trajectories show receptors moving in synaptic and extrasynaptic sites. Figure 1: Photoaffinity probe 1 for tracking GABAA receptors in cells. This thesis also describes a modular synthetic strategy to build additional chemical tools. A "clickable" alkyne gabazine fragment 2 was synthesised and underwent copper catalysed alkyne-azide couplings to give probes 3 and 4. These covalently bind to the receptor through an acrylamide electrophilic moiety, and cleavage of the directing gabazine fragment after UV light leaves a silently-tagged receptor. Further generations of these probes could be used to track unblocked, native receptors in order to compare the effects of antagonism on receptor movement (Figure 2). Figure 2: Photocleavable affinity antagonists 3 and 4 In addition, this thesis discusses a novel photoswitchable antagonist, azo-gabazine 5, which uses the cis-trans photoisomerisation of azobenzene to tune its potency under different wavelengths of light. It is synthesised and used to confer a photoswitching ability onto a native neuronal GABAA receptors in a biological setting (Figure 3). Figure 3: Development of a photoswitchable antagonist to the GABAA receptor, azo-gabazine 5.
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Khan, Abid. "CXCR4 chemokine receptor antagonists : new metallodrugs." Thesis, University of Hull, 2009. http://hydra.hull.ac.uk/resources/hull:10418.
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Chemokine receptors are a target of growing interest for new therapeutic drugs, as their role in multiple disease states has been demonstrated. The CXCR4/ CXCL12 pairing has been implicated in HIV and cancer, as well as chronic inflammatory diseases, including asthma and rheumatoid arthritis. HIV uses CXCR4 or CCR5 receptors in the key binding step of the infection process, leading to the idea that drugs could be developed to block this interaction. Cancer metastasis has also been linked to cellular communication via the chemokine pathways and hence, receptor antagonists could potentially inhibit this important pathway of disease progression. Small synthetic CXCR4 antagonists exist including AMD3100 (Mozobil®/Plerixafor), which has been identified as a potent CXCR4 antagonist exhibiting anti-HIV, anti-inflammatory and anti-tumour activity. Configurationally restricted analogues of AMD3100 complexed to metal ions have improved binding characteristics compared to AMD3100 and its metal complexes. Herein we report the binding of a new class of cyclen, cyclam and tris-cyclam based complexes in vitro. Compounds competed effectively in anti-CXCR4 competition assays with the tricyclam linear complex displaying improved binding characteristics. The difference in activity of the compounds is discussed in relation to the different possible binding interactions that are occurring. Furthermore, a monocyclam derivative conjugated to biotin competed effectively in competition with a CXCR4 mAb, however could not directly be detected via a fluorescent conjugated streptavidin molecule. Our most potent compound to date, copper(II) cross-bridged bicyclam was found to have a significant higher relative residence time in CXCR4 compared to AMD3100 and copper(II) AMD3100 in vitro. Moreover, copper(II) cross-bridged bicyclam was able to totally block CXCL12 induced and partially block serum induced, invasion of CXCR4 positive cancer cells with a higher potency than AMD3100 and copper(II) AMD3100. This shows the potential of using such a drug in the clinic. Using CXCR4 mutants, it has been shown that CXCR4 defective degradation and recycling increases invasion in breast cancer cells. Moreover the development of a multicellular tumour spheroid (MTS) is reported that could be used as a preclinical model in the evaluation of the anti-cancer activity of CXCR4 antagonists.
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Ye, Yulin. "Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists : design and synthesis of IP3 receptor antagonists." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:5e75b5e0-d42a-4b58-9c46-7fabff99e10e.
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Well-regulated Ca2+ signalling is essential for every living organism, and disruption of this signalling can lead to diseases including heart failure, neurological disorders and diabetes. Intracellular Ca2+ levels are regulated by influx of extracellular Ca2+ through channels located in the cell membrane. In addition, release of Ca2+ from intracellular stores also plays an important role in controlling intracellular Ca2+ concentration. Of the three types of intracellular Ca2+ stores that have been characterised those with D-myo-Inositol 1,4,5 trisphosphate receptors (InsP3Rs) showed a close relationship with cell proliferation. Hence, selective blockage of InsP3Rs will allow better understanding of Ca2+ signalling and might also unveil novel treatment for cancers, in the long term. There were no selective InsP3Rs antagonists known at the start of these studies. Based on the crystal structure of InsP3Rs bound to InsP3 and SAR studies of InsP3, we designed and tested several InsP3 analogues.1 Compound 15, 16 and 23 acted as InsP3R antagonists, though their selectivity for InsP3Rs was not completely determined. Furthermore, we also attempted to improve the potency of 16 via substitution at the 1-postion phosphate. By considering the interaction formed between adenophosphostins and InsP3Rs compounds (53-55) were designed and synthesised. In addition, analogues of compound 92, selected from an in silico screen, have led to the discovery of another novel scaffold that acts as an InsP3R antagonist.
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Rečnik, Lisa Maria. "Design and synthesis of selective GluK2 antagonists." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715817.
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Ehalt, Adam. "Synthesis of Selective 5-HT7 Receptor Antagonists." Digital Archive @ GSU, 2011. http://digitalarchive.gsu.edu/chemistry_theses/45.
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The 5-HT7 receptor is the most recent addition to the 5-HT receptor family and has been linked to a variety of physiological and pathophysiological processes. Well established antide-pressant pharmaceuticals have recently been found to activate the 5-HT7 receptor, supporting the role of the 5-HT7 receptor in the antidepressant mechanism. The synthesis of potent selec-tive 5-HT7 receptor antagonists could afford a greater understanding of the 5-HT7 receptor function as well as lead to potential drug candidates.
The synthesis of unfused biheteroaryl derivatives as 5-HT7 receptor ligands has been de-scribed within. These compounds have been tested for biological activity on the 5-HT6 and 5-HT7 receptors. 4-(3’-Furyl)-2-(N-substituted-piperazino)pyrimidines were found to be potent 5-HT7 receptor ligands. 4-(2’-Furyl)-2-(N-substituted-piperazino)pyrimidines have shown high se-lectivity for the 5-HT7 receptor over the 5-HT6 receptor.
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Rayat, Harnak Singh. "The synthesis of potential steroid receptor antagonists." Thesis, University of Warwick, 1995. http://wrap.warwick.ac.uk/56111/.
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The first section of this thesis presents a review of the literature on endocrine hormones, synthetic steroids, and synthetic steroid receptor antagonists. Particular emphasis is placed upon the estrogen, progesterone and glucocorticoid activity of these compounds. The structure, activity and preparation of some progesterone/glucocorticoid receptor antagonists is also reviewed. The second section of this thesis presents a route for the synthesis of 19-aryl substituted androstanes. These compounds have been designed to explore their potential antiprogestational and antiglucocorticoid activity. It is demonstrated that a bulky aromatic functionality may be introduced at the sterically hindered C-19 methyl group, by the nucleophilic attack of an organometallic nucleophile on a 10~-formyl-19-norandrostane, which is suitably protected at positions C-3 and C-17. The subsequent careful manipulation of the C-3 and C-17 functionalities has led to a succesful 11 step synthesis (scheme 4.19) of 17~-hydroxy-17a-(prop-l-yne)-19-(p-N,N- dimethylaminophenyl)androst-5-en-3-one (3.1), which should be of interest for biological evaluation.
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Pillinger, Kathryn. "New antagonists for the Kappa Opioid receptor." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501626.
Full textAbstract:
There has been much evidence in recent years to suggest that the kappa opioid receptor plays a significant role in mediating a number of behavioural disorders including drug abuse and depression. Previous in vitro evaluation within the group of secondary and tertiary amines derived from 2-amino-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-7-ol has suggested that all behave as pure opioid antagonists. These findings prompted further synthetic and pharmacological investigations of this scaffold, with the eventual aim of developing a short-acting selective kappa opioid antagonist to further probe the receptor.
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Kanda, Yasuhiko. "Bioorganic Studies toward Development of Endothelin Antagonists." Kyoto University, 2001. http://hdl.handle.net/2433/150798.
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Jackson, Alexander Rodney. "Pharmacological Evaluation of Cyanoguanidine P2X7 Receptor Antagonists." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17186.
Full textAbstract:
ABSTRACT BACKGROUND AND AIMS: The P2X7 receptor (P2X7R) is an ATP-gated, non-selective cation channel highly expressed on monocytes, macrophages and microglia. Prolonged activation of the P2X7R by ATP leads to cytolytic pore formation and the release of inflammatory mediators including interleukin-1β and prostaglandin E2. Accumulating evidence suggests a role for the P2X7R in neuroinflammation and thus P2X7R antagonists might be useful in diseases including chronic pain, depression and Alzheimer’s disease. Both negative allosteric modulators of the P2X7R, such as the adamantyl benzamides, and orthosteric antagonists, such as the aryl cyanoguanidines, inhibit the ATP-induced release of IL-1β from immune cells. This shared ability to inhibit IL-1β release may explain why no attempts have been made to determine the features which promote binding to the allosteric or orthosteric site. An advantage of targeting the allosteric or orthosteric site might emerge however, if a different agonist of the P2X7R is used. An antimicrobial peptide produced within the human body, LL-37, is also able to activate the P2X7R and yet LL-37 is never used in the characterisation of new series of P2X7R antagonists. The aims of this project were to characterise a novel series of P2X7R antagonists, the adamantyl cyanoguanidines, which have a hybrid structure derived from the adamantyl benzamides and aryl cyanoguanidines. Characterisation of the adamantyl cyanoguanidines should allow determination of the features which promote binding to the orthosteric or allosteric site of the P2X7R, which was one of the primary aims of this project. A second aim was to evaluate the potential of the hybrid series for further development as P2X7R antagonists by considering their potency and physicochemical P a g e | 13 properties. The final aim was to determine if there was any advantage of targeting the orthosteric or allosteric site of the P2X7R particularly with regard to inhibiting LL-37-mediated activation of the P2X7R. METHODS: The potency of adamantyl cyanoguanidines and reference P2X7R antagonists were determined in YO-PRO-1 dye uptake assays and interleukin-1β release assays to develop structure-activity relationships. A potent member of the adamantyl cyanoguanidines and several reference P2X7R antagonists were pharmacologically characterised in Schild assays, washout studies and receptor protection studies. The ability of several negative allosteric modulators and an orthosteric antagonist to inhibit LL-37-induced dye uptake was also examined. RESULTS: More compact adamantyl cyanoguanidines including those with a methylene linker between the adamantyl and cyanoguanidine groups and no linker between the cyanoguanidine group and phenyl ring were more potent than analogues with longer linkers. Ortho-substitution of the phenyl ring or substitution of the ring with 5-quinoline led to increased potency. The potency seen in the dye uptake assay was also seen in the interleukin-1β release assay. A potent member of the series 3-19 was determined to be a slowly reversible negative allosteric modulator as was 1-17 an adamantyl benzamide. The parent aryl cyanoguanidine, A-804598, was confirmed to be an orthosteric antagonist. None of the compounds were able to inhibit LL-37-induced dye uptake. DISCUSSION AND CONCLUSIONS: The determined structure-activity relationships for the adamantyl cyanoguanidines confirm their potential for further development since the series was highly amenable to modification and several potent analogues have favourable physicochemical properties including lower molecular weight. Since 3-19 P a g e | 14 was a negative allosteric modulator despite its structural similarity to A-804598 this suggests the adamantyl group promotes binding to the allosteric site and that cyanoguanidine is a tolerated bioisostere for the acetamide group at the allosteric site. The 5-quinolinyl group, in the appropriate position, facilitates binding to either site. The failure of multiple P2X7R antagonists to inhibit LL-37-induced dye uptake is concerning since LL-37 alone has been shown to induce the release of interleukin-1β from human monocytes. Future research must determine if LL-37 is responsible for cytokine release in vivo and develop small molecule antagonists of the action of LL-37.
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Mercer, Amanda Denise. "Stereochemical studies of H₁-receptor histamine antagonists." Thesis, University of Bath, 1989. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439288.
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Elhebir, Elsamaul Suliman A. "Calcium antagonists-induced lower urinary tract symptoms." Thesis, Curtin University, 2011. http://hdl.handle.net/20.500.11937/305.
Full textAbstract:
Lower urinary tract symptoms (LUTS) are a group of obstructive and irritative urinary symptoms. These include storage, voiding, and post-micturition symptoms. LUTS are prevalent and bothersome in the rapidly growing ageing Australian population and they are associated with a significant deterioration in patients‟ quality of life (QoL). There are a number of risk factors for LUTS. These include medical conditions such as diabetes, stroke, Parkinson‟s disease along with some surgical procedures involving the pelvis or spinal cord. Ageing is also associated with structural and physiologic changes of the lower urinary tract which may contribute to LUTS. LUTS are often inappropriately thought of as a male only problem because of the high prevalence of benign prostatic hypertrophy (BPH) in older men; however, the development of LUTS is not gender specific and women may develop LUTS following menopause or post-hysterectomy.A number of drugs have been found to affect the bladder and the micturition process including the commonly prescribed calcium antagonists (CAs). CAs were the ninth most frequently prescribed group of drugs in Australia in the year 2008, with more than seven million prescriptions dispensed during that year. Apart for their effects relaxing the detrusor smooth muscle hence impairing micturition, CAs can also increase the production of urine through their natriuretic effect and cause constipation through their muscle relaxation and anti-cholinergic activity, which can further exacerbate LUTS. The association between CA use and LUTS is not well investigated. The aim of this research was to investigate the association between CA use and LUTS in males and females. Further to assess the consequences of CA-associated LUTS on users‟ QoL and receipt of treatment for LUTS.During the Phase 1 of this research, a review was conducted for all reports submitted to the Adverse Drug Reaction Advisory Committee (ADRAC) of Australia up until January 2009. The review revealed 80 reported cases (females 45 [56.2%], males 34 [42.5%]). The mean age of the patients was 63.4±14.1 years (range 36-99 years). Amlodipine was the most frequently reported drug and lercanidipine was the least reported. Pollakiuria and other obstructive urinary symptoms were the most commonly reported symptoms. More than half of the patients (46; 57.5%) had complete resolution of their LUTS after medication discontinuation while 10 (12.5%) patients did not recover; an outcome was not reported for the remaining 24 (30%) patients. The review highlighted the importance of including females and younger patients in future studies. Further, it also suggested that LUTS associated with CA use is reversible in the majority of cases following medication discontinuation.A study was conducted, in Phase 2 of this research, to investigate the relationship between CA-use and LUTS amongst hospitalised medical patients at Royal Perth Hospital. The study also looked at the impact of CA-associated LUTS on patients‟ urological QoL. A demographic questionnaire was used along with the validated International Prostate Symptoms Score (IPSS) -for measuring LUTS- and BPH Impact Index (BII) -for measuring urinary related QoL-. A total of 278 patients (151 males, 127 females, mean age 72.1±13.7 years) were recruited into the study. About one third of the patients were using CAs. The males mean IPSS of 12.2 ± 8.19 was higher compared to that of the females (9.74 ± 6.59, p = 0.007), indicating significantly worse LUTS. CA-users were found to have a statistically significantly higher mean IPSS (15.22 ± 8.1) compared to non-CA-users (9.25 ± 6.6, p < 0.0001). CA-users were found to be more likely to suffer from severe and moderate-to-severe LUTS (p < 0.0001 for both).The association between CA use and LUTS was not a class effect. A strong association emerged between amlodipine/nifedipine and diltiazem/verapamil use and severe LUTS, adjusted odds ratios (AOR) of 9.8 (95% CI, 3.98-24.34) and 8.2 (95% CI, 1.93-34.92), respectively. However, none of the patients receiving felodipine/lercanidipine suffered from severe LUTS. A similar association was also observed with moderate-to-severe LUTS.This increased risk of suffering from moderate and/or severe LUTS was matched by a similar deterioration of QoL measured by patients‟ level of dissatisfaction (AOR amlodipine/nifedipine 2.80 [95% CI, 1.68-4.68] and diltiazem/verapamil 3.65 [95% CI, 1.02-13.01]). The AOR was not statistically significant for felodipine/lercanidipine, 1.12 (95% CI, 0.47-2.67). Further, an estimated 22.4% of the CA-users group were taking medications to treat LUTS compared to 9.3% in the non-CA-users group, p = 0.003. Both male and female CA-users were three times more likely to be on an alpha-blocker than non-CA-users (p=0.0001). Male CA-users were two times more likely to have undergone urological surgeries (Fisher exact test, p=0.07) whilst female CA-users were nine times more likely (Fisher exact test, p=0.029).In Phase 3 of the research, a prescription sequence symmetry analysis was conducted in collaboration with the Department of Veteran affairs (DVA), Australia. This method was developed to create signals of a potential adverse event of drugs. The DVA prescription database for a 5-year period (2004-2008) was used to estimate the sequence ratio and the adjusted sequence ratio (ASR). The data revealed that there was about two-fold-increase in prazosin use after the first CA commencement, ASR 1.91 (95% CI 1.69-2.17). The use of urinary antispasmodics was also higher after CA use, ASR of 1.31 (95% CI 1.15-1.49). These results present a strong signal of an association between CA use and prazosin and urinary antispasmodic use (markers for LUTS).The final phase of the research involved an audit of dispensing records of 1,548 patients from a number of Australian residential aged care facilities (RACFs). In this study, CAs users were more likely to be on alpha blockers (as a group of drugs), AOR 2.11 (95% CI 1.05-4.26); and on prazosin, AOR 4.22 (95% CI 1.76-10.12). CA-users were also found to be more likely to be on urinary antispasmodics, AOR 2.18 (95% CI 1.32-3.61).The research had demonstrated a strong association between CA use and LUTS. This association could lead to a significant deterioration in QoL and it does not appear to be a class effect. CA-users are more likely to have more severe LUTS and to be on a treatment for LUTS or to have undergone urological interventions.xviiBased on these findings it is recommended that CA-users should be monitored for the development or the deterioration of LUTS. Moreover, CAs should always be considered as a possible cause for LUTS and consideration to be given to ceasing or switching CAs.
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Bodenstein, Johannes. "Antagonism by selected classical irreversible competitive antagonists : an investigation into the proposed non-specific mechanisms involved / Johannes Bodenstein." Thesis, North-West University, 2003. http://hdl.handle.net/10394/92.
Full textAbstract:
Many irreversible antagonists are known to bind irreversibly to pharmacological
receptors. However, few studies suggest that these irreversible antagonists may also
display irreversible non-specific antagonism by binding irreversibly to non-syntopic
binding sites on the receptor macromolecule, whereby they modulate the signal
transduction of these receptors or reduce the agonist binding affmity.
The aim of this study was to investigate whether the classical irreversible antagonists
phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible nonspecific
antagonism at various G protein-coupled receptor (GPCR) types. In addition,
the subcellular mechanism whereby benextramine displays irreversible non-specific
antagonism was investigated.
Three cell lines were employed to investigate the antagonism by these irreversible
antagonists: Chinese hamster ovary (CHO-K1) cells transfected to express the porcine
a2A-adrenoceptor (a2A-AR) at higher (a2A-H) or lower (a2A-L) numbers, human
neuroblastoma (SH-SY5Y) cells that endogenously express muscarinic acetylcholine
receptors (mACh-Rs), and SH-SY5Y cells transfected (5HT2A-SH-SY5Y)o express
the human 5HT2A-serotonirne ceptor (5HTZA-R).C ells of the appropriate cell line were
pre-treated at the appropriate concentrations and incubation times with an appropriate
irreversible antagonist, with or without an appropriate reversible competitive antagonist
at a sufficient concentration to protect the specific receptors. This was followed by
washing procedures with drug-free media to rinse any unbound or reversibly bound
drugs from the cells. When appropriate, cell membranes were prepared. Receptor
function was evaluated by measuring whole-cell [3H]-cAMP or [3H]-IPx acumulation,
or the binding of [35S]-GTPyS to membraness. Receptor concentrations were
determined from radioligand-binding assays. In addition, the constitutive [35S]-GTPyS binding to Go protein before and after pre-treatment with benextramine was investigated.
Results suggest that phenoxybenzamine (100 uM, 20 minutes) and benextramine (10
uM, 20 minutes) display irreversible non-specific antagonism at a2A-ARs when measuring Gi-mediated effects in a2A-L cells, but the affinity for a2A-ARs in a2A-H cells was not changed. In addition, it was found that the observed irreversible nonspecific antagonism by benextramine appears to be time- and concentration-dependent.
When the mechanism of irreversible antagonism by benextramine was further investigated, benextramine reduced the binding of [35S]-GTPyS to a2A-H membranes with protected a2A-ARs, but did not modulate the constitutive binding of [35S]-GTPyS to Go. In addition, benextramine displays irreversible non-specific antagonism by
inhibiting the G,-mediated effects of a2A-ARs in a2A-H cells and the Gq-mediated
effects of mACh-Rs or 5HT2A-Rs in SH-SY5Y or 5HT2A-SH-SY5Y cells respectively.
4-DAMP mustard (100 uM, 20 minutes) did not display irreversible non-specific
antagonism at mACh-Rs in SH-SY5Y cells, but irreversible non-specific antagonism
was observed when the incubation time was increased (100 uM, 60 minutes).
In conclusion it was found that phenoxybenzamine, benextramine and 4-DAMP
mustard display irreversible non-specific antagonism at typical experimental
conditions. These findings confirm concerns in literature and supports the possibility
that more irreversible antagonists could display irreversible non-specific antagonism,
and that could influence the interpretation of data obtained with such drugs. In
addition, benextramine may prove to be a useful experimental drug in studying GPCR
signalling.Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.
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Hunter, Allison M. "Smac-based antagonists of the inhibitors of apoptosis." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/29351.
Full textAbstract:
Apoptosis signal pathways converge on the Caspases, a family of proteases that form a self-amplifying cascade, the activation of which generates the characteristic morphological and biochemical features of apoptotic cell death. The Inhibitors of Apoptosis (IAPs) are a family of proteins that bind and inactivate Caspases at both the initiation and terminal effector stages of this cascade. Over-expression of IAPs, as observed in cancer cell lines and tumour biopsy samples, results in a cellular phenotype of resistance to a variety of apoptotic stresses including chemotherapeutic drugs and irradiation. One negative regulator of IAP function, Smac (second mitochondrial activator of Caspases a.k.a.Diablo) has been identified as a mitochondrial protein that is processed and released concomitantly with cytochrome c following an apoptotic stress. Proteolytic processing of the mitochondrial signal peptide sequence generates a novel amino terminus that interacts with XIAP and disrupts XIAP-meditated Caspase-9 inhibition. By disrupting the interaction of XIAP with Caspase-9, Smac is believed to promote apoptotis. Furthermore, the structure determinations of XIAP, in conjunction with either Caspases or Smac, have led to the identification of a critical pocket and groove on the surface of each BIR domain ( Baculovirus IAP Repeat). Within XIAP BIR3, the binding pocket interacts with Caspase-9 and can be disrupted by the presence of Smac, which competes for the same site.
In this thesis work, the utility of Smac as a chemo-sensitizing agent for the treatment of cancer was enhanced by three different strategies. The first approach involved the development and characterization of an ubiquitin-Smac fusion system that circumvents the targeting of Smac to the mitochondria and results in the expression of a fully mature, biologically active Smac protein. The second approach entailed developing a strategy for increasing the affinity of Smac binding to the IAPs. A random peptide phage display screen was used to identify novel, high affinity peptide ligands that bind to the IAP-BIR3 motifs. These peptide sequences were similar in structure to the amino terminus of Smac and Caspase-9. The data generated from these two approaches showed that both over-expressed, mature Smac and Smac-like peptide sequences bind to the IAPs in vitro and in vivo and sensitize cells to chemotherapeutic drugs. The third and final approach involved developing a Smac system that was a more potent apoptosis-inducer than wild-type Smac, which would be predicted to have greater therapeutic potential. It has been shown that Smac interactions with the IAP BIR domains may accelerate IAP auto-ubiquitination and destruction via the IAP carboxy terminal RING (Really Interesting New Gene) domain. Adding an IAP-RING domain to the carboxy terminus of Smac was predicted to enhance IAP degradation while maintaining the IAPs in a non-functional protein complex. Indeed, it was observed that generating a Smac protein with RING-conferred E3 ligase activity significantly decreased IAP levels, with a concomitant increase in the sensitivity to apoptosis in the presence of chemotherapeutic agents.
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Beauglehole, Anthony Robert, and anthony@adenrx com. "N3-substituted xanthines as irreversible adenosine receptor antagonists." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20080612.084330.
Full textAbstract:
8-Cyclopentyl-3-(3-(4-fluorosulfonylbenzoyl)oxy)propyl-propylxanthine (44, FSCPX) has been reported to exhibit potent and selective irreversible antagonism of the A1 adenosine receptor when using in vitro biological preparations. However, FSCPX (44) suffers from cleavage of the ester linkage separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine pharmacophore when used in in vivo biological preparations or preparations containing significant enzyme activity, presumably by esterases. Cleavage of the ester linkage renders FSCPX (44) inactive in terms of irreversible receptor binding. In order to obtain an irreversible A1 adenosine receptor antagonist with improved stability, and to further elucidate the effects of linker structure on pharmacological characteristics, several FSCPX (44) analogues incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety were targeted, where the labile ester linkage has been replaced by more stable functionalites. In particular, ether, alkyl, amide and ketone linkers were targeted, where the length of the alkyl chain was varied from between one to five atoms.
Synthesis of the target compounds was achieved via direct attachment of the N-3 substituent to the xanthine. These compounds were then tested for their biological activity at the A1 adenosine receptor via their ability to irreversibly antagonise the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX, ( 9) to the A1 adenosine receptor of DDT1 MF-2 cells. For comparison, the xanthines were also tested for their ability to inhibit the binding of [3H]-4-(2-[7-amino-2-{furyl} {1,2,4}- triazolo{2,3-a} {1,3,5}triazin-5-ylamino-ethyl)]phenol ([3H]ZM241385, 36) to the A2A adenosine receptor of PC-12 cells. The results suggest that the length and chemical composition of the linker separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine ring contribute to the potency and efficacy of the irreversible A1 adenosine receptor ligands. Like FSCPX (44, IC50 A1 = 11.8 nM), all derivatives possessed IC50 values in the low nM range under in vitro conditions. Compounds 94 (IC50 A1 = 165 nM), 95 (IC50 A1 = 112 nM) and 96 (IC50 A1 = 101 nM) possessing one, three and five methylene spacers within the linkage respectively, exhibited potent and selective binding to the A1 adenosine receptor versus the A2A adenosine receptor. Compound 94 did not exhibit any irreversible binding at A1 adenosine receptors, while 95 and 96 exhibit only weak irreversible binding at A1 adenosine receptors. Those compounds containing a benzylic carbonyl separating the 4-(fluorosulfonyl)phenyl moiety from the xanthine ring in the form of an amide (119, IC50 A1 = 24.9 nM, and 120, IC50 A1 = 21 nM) or ketone (151, IC50 A1 = 14 nM) proved to be the most potent, with compound 120 exhibiting the highest selectivity of 132-fold for the A receptor over the A2A receptor. compounds 119, 120 and 151 also strongly inhibited the binding of [3H]DPCPX irreversibly (82%, 83% and 78% loss of [3H]DPCPX binding at 100 nM respectively). compounds 120 and 151 are currently being evaluated for use in in vivo studies.
Structure-activity studies suggest that altering the 8-cycloalkyl group of A1 selective xanthines for a 3-substituted or 2,3-disubstituted styryl, combined with N-7 methyl substitution will produce a compound with high affinity and selectivity for the A2A adenosine receptor over the A1 adenosine receptor. Compound 167 (IC50 A2A = 264 nM) possessing 8-(m-chloro)styryl substitution and the reactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine ring via an amide linker in the 3-position (as for 119 and 120), exhibited relatively potent binding to the A2A adenosine receptor of PC-12 cells, with a 16-fold selectivity for that receptor over the A1 adenosine receptor. However, compound 167 exhibited only very weak irreversible binding at A2A adenosine receptors.
Overall, at this stage of biological testing, compound 120 appears to possess the most advantageous characteristics as an irreversible antagonist for the A1 adenosine receptor. This can be attributed to its high selectivity for the A1 adenosine receptor as compared to the A2A adenosine receptor. It also has relatively high potency for the A1 adenosine receptor, a concentration-dependent and selective inactivation of A1 adenosine receptors, and unbound ligand is easily removed (washed out) from biological membranes. These characteristics mean compound 151 has the potential to be a useful tool for the further study of the structure and function of the A1 adenosine receptor.
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Fischer, Bradford D. Dykstra Linda A. "Interactions between opioid agonists and glutamate receptor antagonists." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1694.
Full textAbstract:
Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Psychology Behavioral Neuroscience." Discipline: Psychology; Department/School: Psychology.
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McRobbie, Graeme Walter John. "Configurationally restricted bis-tetraazamacrocyclic complexes : chemokine receptor antagonists." Thesis, University of Hull, 2009. http://hydra.hull.ac.uk/resources/hull:5855.
Full textAbstract:
The chemokine receptor CXCR4 is a trans-membrane protein which has been implicated in many physiological and pathological processes including cancer, rheumatoid arthritis and most significantly HIV replication. CXCR4 plays a vital role in embryonic development but is not essential at the post-development stage; therefore, it has been identified as a potential therapeutic target. Bis-macrocyclic drugs (e.g. AMDS 100) bind to aspartate residues on the CXCR4 surface and inhibit HIV replication by blocking the interaction of gp!20/gp41 with the protein. The incorporation of transition metals (e.g. zinc(II) and copper(II)) into the macrocyclic cavity increases anti-viral potency. The addition of a bridging ethylene unit to the macrocyclic framework locks the complex into a single configuration, potentially optimising the interaction with the receptor. A series of configurationally restricted macrocyclic compounds have been prepared utilising bis-aminal chemistry. Characterisation by X-ray crystallography and X-ray absorption spectroscopy has confirmed that the complexes possessing an ethylene bridge between adjacent nitrogen atoms are fixed in the trans-II configuration and that complexes containing an ethylene bridge between non-adjacent nitrogen atoms adopt the cis-V configuration. In addition, solution EXAFS has been used as a model to probe the binding of the complexes to aspartate residues on the receptor surface. The zinc(II) trans-II and copper(II) cis-V complexes reported here are more potent against HIV replication than AMDS 100 (IC₅₀ values against IIIB ; 0.00208 µM, 0.00491 µM and 0.018 µM respectively), confirming the importance of coordination interactions for potent binding to CXCR4 and also validating the strategy of configurationally fixing the macrocyclic unit for optimising receptor binding. It is believed that both thermodynamic and kinetic properties are important for effective binding to CXCR4.
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O'Neill, Hugh Charles. "Structure-activity studies on alphaâ†2-adrenoceptor antagonists." Thesis, Liverpool John Moores University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238727.
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Mabrouka, Maamra Bent Ahmed Ben Laid. "Truncated cytokine receptors and antagonists : signalling and trafficking." Thesis, University of Sheffield, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251278.
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Bailey, Louise Lyn. "The development of Interleukin-6 specific peptide antagonists." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299390.
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Ahmed, Mohaned S. A. "New C-C chemokine receptor type 7 antagonists." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14623.
Full textAbstract:
Chemokines are chemotactic cytokines which play an important role in the migration of immune cells to distant tissues or compartments within tissues. These proteins have also been demonstrated to play a major role in cancer metastasis. The C-C chemokine receptor type 7 (CCR7) is a member of the chemokine receptor family. CCR7 along with its ligands CCL19 and CCL21 plays an important role in innate immune response by trafficking of lymphocytes. In cancer, tumour cells expressing CCR7 migrate to lymphoid organs and thus disseminate to other organs. Neutralizing the interactions between CCL21/CCR7 would therefore be expected to inhibit the progression and metastasis of many different types of cancer to regional lymph nodes or distant organs. Our objective was to identify a potent small molecule antagonist of CCR7 as a prelude to the investigation of the role of this axis in cancer metastasis. In this study, we provided a brief description of chemokines and their role in health and disease with an emphasis on the CCR7/CCL19/CCL21 axis, as well as identification of a CCR7 antagonist “hit”. The potency of the CCR7 antagonist “hit” was optimised by synthesizing different CCR7 antagonist analogues. The “hit” optimization process has led to discover the most active compound amongst a series of different analogues which have the ability to bind and block CCR7 receptor. The efficacy of the most active compound and other analogues were evaluated in vitro using a calcium flux assay which is based on detecting fluorescent light emitted upon release of calcium ions. To identify a suitable cell line, which expresses CCR7 and capably respond to it, amongst a panel of cell lines for in vitro assessment of potency of synthesised compounds, we used Western blot assay and later by flow cytometry assay. The activity and selectivity of the most effective compound against CCR7 receptor was evaluated in vitro by other functional assays such as “configured agarose spot assay” and scratch assay. We first configured the existing under agarose assay to fulfil our requirements and then used it to assess activity and selectivity of compounds. The configured agarose spot assay also describes the application of the agarose spot for evaluation of cells chemotactic response to multiple chemokines under identical experiment conditions.
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Cooper, David Gwyn. "Structure-activity in pyridine-containing histamine receptor antagonists." Thesis, Imperial College London, 1987. http://hdl.handle.net/10044/1/38269.
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Wood, Martin David Hugh. "Synthesis and evaluation of selective thiamin diphosphate antagonists." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612333.
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Stracthan, Anna J. "Pharmacological activity of novel peptidic C5a receptor antagonists /." St. Lucia, Qld, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16482.pdf.
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Arigoni, Chiara. "Acute treatment of arterial hypertension with calcium antagonists /." [S.l : s.n.], 1986. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Williams, Ian Andrew. "Investigation of aminotetralins as novel opioid receptor antagonists." Thesis, University of Bath, 2006. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438651.
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Musa, Muftah Miloud A. "Structure activity relationship studies of new ethylene antagonists." Thesis, Curtin University, 2016. http://hdl.handle.net/20.500.11937/77805.
Full textAbstract:
Ethylene antagonists provide one of the most effective methods to reduce postharvest losses of horticulture produce. The understanding of the mode of action of 1-methylcyclopropene led to the discovery of a new class of ethylene antagonist. Cycloproparenes, benzocyclopropene and 1H-naphtho[b]cyclopropene were prepared and showed excellent inhibition of the effect of ethylene on some fruits and waxflowers.
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Rosick, Edward R. (Edward Rudolph). "Effect of Calcium Channel Antagonists and Other Agents on Olfactory Reception." Thesis, North Texas State University, 1985. https://digital.library.unt.edu/ark:/67531/metadc503999/.
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The role of Ca++ in olfactory responses was investigated with inorganic and organic calcium channel antagonists. Electrophysiological responses to odorants were recorded from frog olfactory mucosa before and after aerosol application of different agents. Electroolfactogram responses were blocked by certain inorganic ions with the order of effectiveness Zn++ >Ln+++>Cd++>Ca++>Co++>Sr++>Mg++. Ba++ potentiated olfactory responses, and is known to potentiate calcium channel-mediated responses in other tissues. Certain local anesthetics which are thought to act through calcium channel blockade were inhibitory to olfactory responses, with the order of effectiveness being dibucaine>tetracaine>procaine. These data support the idea that Ca++ is involved in olfaction, perhaps acting as a current carrier and/or a second messenger. Preliminary experiments on channel localization were performed using a silicon-labeled amine. Attempts to localize the silicon label were inconclusive, although silicon was detected in the olfactory tissue.
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Kandepedu, Hemachandra Nishanth. "Synthèse et évaluation de nouveaux squelettes de molécules potentiellement antagonistes du récepteur au CGRP : application à la douleur chronique." Thesis, Clermont-Ferrand 2, 2015. http://www.theses.fr/2015CLF22627.
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Analgésiques opiacés et les antidépresseurs tricycliques (ATC) sont deux grandes classes d'agents thérapeutiques qui sont utilisés pour soulager les symptômes dus au nociception chronique. Mais ces agents chimio thérapeutiques présentent des effets secondaires comme la constipation, dépendance physique plus soulagement de la douleur insuffisante. D'où des complications aggravent la nécessité de concevoir une molécule qui agit sur nouvelle cible en vue de surmonter les effets secondaires causés par la classe dit ci-dessus de médicaments. Pendant ce temps, la distribution du peptide lié au gène de la calcitonine (CGRP), un neuropeptide de 37 acides aminés deux dans le système nerveux central et périphérique et son rôle dans la douleur viscérale a ouvert une nouvelle porte d'entrée pour le traitement de la douleur nociceptive viscérale. Ainsi, l'objectif principal du projet de fusionner propriété antagoniste de CGRP ainsi que la propriété antidépresseur dans une seule molécule, pour fournir un effet de synergie et de traiter les maladies chroniques, inflammatoires et négligées comme le syndrome du côlon irritable (IBS) et la maladie de CrohnOpiate analgesics and tricyclic antidepressants (TCAs) are two major classes of therapeutic agents which are used to alleviate symptoms due to chronic nociception. But these chemotherapeutic agents pose side effects like constipation, physical dependence along with insufficient pain relief. Hence these complications aggravate the necessity of designing a molecule which acts on new target in order to overcome the side effects caused by the above said class of drugs. Meanwhile, the distribution of Calcitonin Gene Related Peptide (CGRP), a 37 amino acid neuropeptide both in central and peripheral nervous system and its role in visceral pain has opened up a new gateway for treating visceral nociceptive pain. Thus, the main aim of the project was to merge CGRP antagonist property as well as Antidepressant property in a single molecule, to provide a synergistic effect and to treat Chronic, inflammatory and neglected diseases like Irritable bowel syndrome (IBS) and Crohn’s disease
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Dawson, William A. J. M. "Cereal root and stem-base fungi and effects of seed treatment fungicides." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312056.
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Erkkila, Brian E. "Molecular determinants of picrotoxin inhibition." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/erkkila.pdf.
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Whitcroft, I. "The effects of alpha- and beta-adrenoreceptor antagonists and calcium channel antagonists on glucose and lipid metabolism in non-insulin dependant diabetics." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382150.
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Petersson, Klas. "Population Pharmacodynamic Modeling and Methods for D2-receptor Antagonists." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-172540.
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Early predictions of a potential drug candidate’s time-course of effect and side-effects, based on models describing drug concentrations, drug effects and disease progression, would be valuable to make drug development more efficient. Pharmacodynamic modeling can incorporate and propagate prior knowledge and be used for simulations of different scenarios. In this thesis three population pharmacodynamic models were developed to describe the antipsychotic effects and the side-effects prolactin elevation and Extra Pyramidal Symptoms (EPS) following administration of D2-receptor antagonists, commonly used in the treatment of schizophrenia. Model parameter estimates of prolactin elevating potencies of six compounds correlated with in vitro values of receptor affinities, and parameters related to diurnal prolactin variation and tolerance were similar for the different compounds. The developed prolactin model can thereby be used to predict the time-course of prolactin elevation in patients for a drug candidate using information on in vitro affinity to the D2-receptor. Furthermore, the clinical antipsychotic effect and the prolactin elevation was found to correlate on the individual level for the three antipsychotic compounds investigated and a quantitative relation between D2-receptor occupancy in the brain and prolactin elevation was established. These results support the use of prolactin concentrations as a biomarker in drug development or for individual dose adjustments in clinical care. The developed model for spontaneously reported EPS adverse events, following treatment with one of five antipsychotics drugs, characterized both the duration and severity of EPS. The model successfully described both the proportions and number of transitions between severity grades and was shown to adequately simulate longitudinal categorical EPS data. Complex pharmacodynamic models are often associated with long estimation times and non-normal distributions of individual parameters. A method for shortening computation times by substituting differential equations for difference equations was evaluated and shown to be valuable for some models. In addition, transformation of distributions allowed for non-normal distributions of between-subject variability to be better characterized and thereby simulation properties were improved. In conclusion, population pharmacodynamic models for a range of D2-receptor antagonists were developed and together with the investigated methods the models can facilitate prediction of effects and side-effects in drug development.
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Sagan, Ewelina Nina. "The influence of P2Y12 antagonists on vascular NO signalling." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/48547/.
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P2Y12 antagonists are pharmacological agents used clinically in advanced stages of coronary artery disease in order to inhibit ADP-induced activation and aggregation of platelets and prevent deadly thrombotic events. Of the orally-prescribed P2Y12 antagonists available clopidogrel is the most established, it exhibits an excellent safety track record and is a popular drug, and was accredited for years the second-best selling drug in the world. However, since clopidogrel was introduced to the market in 1997 many pleiotropic effects have been noticed, which suggest other off-target yet beneficial effects in addition to its anti-platelet effects. The overall hypothesis being tested in this body of work was that P2Y12 antagonists, clopidogrel in particular, have the positive influence on vascular NO signalling. A vascular model was set up using isolated rabbit aortae in which clopidogrel enhanced NO donor-induced vasorelaxation. Although the precise mechanism was not found, the effect was independent of P2Y12 receptors and possibly linked to decreased superoxide production and improved anti-oxidant/inflammatory status in vessels. This finding might be relevant for patients receiving concomitant therapy with organic nitrates and clopidogrel. In vitro studies revealed novel S-nitrosation properties of P2Y12 antagonists, surprisingly without the need for metabolism to their active form. Newly synthesized SNO derivatives of clopidogrel and prasugrel were more potent in inhibition of platelet aggregation and induction of vasodilation than their parental forms. Although the formation of drug-SNO species has to be confirmed in vivo, they have a potential to increase NO bioavailability in patients. Clopidogrel administration to coronary artery disease patients resulted in upregulated plasma levels of nitrite and cGMP after 2 h-intake of a loading dose, which were further increased after 3 days of a maintenance therapy. This effect was never shown before in man and most likely reflects improved endogenous NO production, but also providing additional protection from the effects of nitrite at the same time. Taken together, the results of this thesis clearly demonstrate the influence of clopidogrel on vascular response to NO as well as NO production, metabolism and bioavailability. It is important to identify these alternative pathways especially in the current era with alternative P2Y12 antagonists that overcome some of the limitations of clopidogrel but may not share all the beneficial properties.
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Malinauskas, Tomas. "Structural and functional studies of Wnt signalling pathway antagonists." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558451.
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Wnt morphogens control embryonic development and adult tissue homeostasis. Deregulation of the Wnt signalling pathway leads to human diseases. This thesis covers work on two antagonists of the Wnt signalling pathway, Wnt inhibitory factor 1 (WIF-l) (Chapters 1 to 5) and secreted Frizzled-related protein 1 (sFRP-l) (Chapters 1 and 6). In vertebrates the N- terminal WIF domain of the six-domain WIF-1 and the cysteine-rich domain of the two- domain sFRP-1 bind to Wnt proteins and inhibit signal transduction. My human WIF domain crystal structure reveals a novel binding site for phospholipid. Two acyl chains of the phospholipid extend deep into the domain while the lipid head group is surface exposed. Biophysical and cellular assays, combined with structure-guided mutagenesis, indicate a WIF domain Wnt-binding surface proximal to the lipid head group, but also implicate the five epidermal growth factor (EGF)-like domains (EGFs I-V) in Wnt binding. The crystal structure of the six-domain WIF-l reveals EGFs I-V wrapped-back to interface with the WIF domain at EGF Ill. Binding studies locate a heparan sulfate proteoglycan-binding site in EGFs II-V, consistent with highly conserved, positively charged residues on EGF IV. My human sFRP-1 cysteine-rich domain crystal structures reveal a conserved hydrophobic homodimer interface, conformationally variant N- and C-termini, and a conformationally invariant, putative Wnt-binding site. The site is located proximal to a positively charged surface region, which is consistent with the observed sFRP-1 cysteine-rich domain binding to heparin and heparan sulfate. The combination of heparan sulfate proteoglycan- and Wnt-binding properties suggests a model for WIF-1 and sFRP-1 localisation, and signalling inhibition, within Wnt morphogen gradients. The findings described in this thesis provide insights into the medically-important mechanisms of Wnt signalling pathway.
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Bartrup, Julian Timothy. "Studies on adenosine and calcium antagonists in rat brain." Thesis, University of Glasgow, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235553.
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Slaughter, Kimari. "Synthesis and Development of Potential CB1 Receptor Neutral Antagonists." ScholarWorks@UNO, 2012. http://scholarworks.uno.edu/td/1483.
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Cannabis and its derivatives have been used for both medicinal and recreational purposes. The study of this plant led to the discovery of over 60 cannabinoids, found exclusively in cannabis, that contribute to the behavioral effects of cannabis use, the most common is delta-9-tetrahydrocannabinol. Cannabinoid receptors function to increase activity in the mesolimbic dopamine reward system. Dopamine is a neurotransmitter that plays a major role in addition and its regulation plays a crucial role in mental and physical well-being. There is evidence that CB1 receptors are important to the reinforcing effects and the development of physical dependence on opiate drugs. Studies have shown that increased levels of dopamine are consistent with addiction while reduced levels lead to a decline in recreational use.
The goal of this research is to design, synthesize and develop potential CB1 receptors that exhibit a neutral cannabinoid antagonist pharmacological profile.
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Klein, Amanda Crystal. "Development of a Pharmacological Screen for M5 Muscarinic Antagonists." University of Toledo Health Science Campus / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=mco1311090042.
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