Journal articles: 'Neurokinin'

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Dobbins, David E. "Neuropeptide modulation of lymphatic smooth muscle tone in the canine forelimb." Mediators of Inflammation 1, no. 4 (1992): 241–46. http://dx.doi.org/10.1155/s096293519200036x.

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Neurokinin A and B are putative inflammatory mediators. We assessed their ability to alter prenodal lymphatic resistance. Intralymphatic neurokinin A (3.0 × 10−6, 3.0 × 10−5and 3.0 × 10−4mol l−1) significantly constricted lymphatics at the two highest doses. Preliminary experiments suggested that neurokinin B might dilate lymphatics. To test this, lymphatic pressure was increased by norepinephrine (3.1 × 10−6mol l−1). Neurokinin B (2.7 × 10−4mol l−1) was then infused intralymphatically during norepinephrine infusion. Norepinephrine increased perfusion pressure from 5.6 ± 0.6 mmHg to 12.1 ± 1.4 mmHg. Subsequent infusion of neurokinin B significantly decreased lymphatic perfusion pressure from 11.9 ± 1.3 mmHg to 9.9 ± 1.1 mmHg. These data indicate that neurokinin A and B can alter lymphatic resistance and are consistent with the hypothesis that lymph vessel function may be subject to modulation by neurokinins.

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Lundberg, Jan M. "Tachykinins, sensory nerves, and asthma—an overview." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 908–14. http://dx.doi.org/10.1139/y95-125.

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Tachykinin peptides, substance P (SP) and neurokinin A (NKA), are released from airway sensory nerves upon exposure to irritant chemicals and endogenous agents including bradykinin, prostaglandins, histamine, and protons. The released neuropeptides are potent inducers of a cascade of responses, including vasodilatation, mucus secretion, plasma protein extravasation, leukocyte adhesion–activation, and bronchoconstriction. Neurokinin 1 receptors (preferably activated by SP) seem to be most important for inflammatory actions, while neurokinin 2 receptors (preferably activated by NKA) mediate bronchoconstriction. Species differences exist whereby rat and guinea-pig have a more developed neurogenic inflammation response than normal human airways. However, disease states such as inflammation or viral infections lead to enhanced peptide synthesis and (or) increased sensory nerve excitability. Together with increased neurokinin 1 receptor synthesis and loss of major tachykinin-degrading enzymes such as neutral endopeptidase in airway inflammation, this suggests that recently developed, orally active nonpeptide neurokinin receptor antagonists could have a therapeutic potential in asthmatic patients.Key words: neurokinins, sensory nerves, inflammation, bronchoconstriction, receptors.

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Kimball, E. S., F. J. Persico, and J. L. Vaught. "Substance P, neurokinin A, and neurokinin B induce generation of IL-1-like activity in P388D1 cells. Possible relevance to arthritic disease." Journal of Immunology 141, no. 10 (November 15, 1988): 3564–69. http://dx.doi.org/10.4049/jimmunol.141.10.3564.

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Abstract Near nanomolar concentrations of substance P induce production of IL-1 or an IL-1-like activity in the mouse macrophage cell line P388D1. Moreover, this could be accomplished with the carboxyl-terminal octapeptide substance P4-11, and could be inhibited with the substance P antagonist [D-Pro2, D-Trp7,9]-substance P. Two other mammalian neurokinins, neurokinin A and neurokinin B, were also found to induce secretion of IL-1-like activity in P388D1 cells. These findings suggest that activation of immune cells by neuromodulators can contribute to the maintenance of the chronic inflammatory state and the immunopathology observed in arthritic disease mediated by IL-1. The results also suggest that one approach to the treatment of rheumatoid arthritis might be to attempt to inhibit the local effects of immuno-modulatory neuropeptides, specifically the neurokinins, in affected joints.

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Edvinsson, Jacob CA, Philip V. Reducha, Majid Sheykhzade, Karin Warfvinge, Kristian A. Haanes, and Lars Edvinsson. "Neurokinins and their receptors in the rat trigeminal system: Differential localization and release with implications for migraine pain." Molecular Pain 17 (January 2021): 174480692110594. http://dx.doi.org/10.1177/17448069211059400.

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Substance P (SP) and calcitonin gene-related peptide (CGRP) have both been considered potential drug candidates in migraine therapy. In recent years, CGRP receptor inhibition has been established as an effective treatment, in particular as a prophylactic for chronic migraine. Curiously, inhibition of neurokinin receptor 1 (NK1R) failed to alleviate acute migraine attacks in clinical trials, and the neurokinins were consequently abandoned as potential antimigraine candidates. The reason behind this has remained enigmatic. Utilizing immunohistochemistry and semi-quantitative cell counts the expression of neurokinins and their associated receptors was examined in the rat trigeminal ganglion. Immunohistochemistry results revealed SP co-localization in CGRP positive neurons and C-fibres, where it mainly concentrated at boutons. Neurokinin A (NKA) was observed in a population of C-fibres and small neurons where it could co-localize with SP. In contrast, neurokinin B (NKB) did not co-localize with SP and was observed in large/medium sized neurons and Aδ-fibres. All neurokinin receptors (NK1-3R) were found to be expressed in a majority of trigeminal ganglion neurons and A-fibres. The functional release of SP and CGRP in the trigeminovascular system was stimulated with either 60 mM K+ or 100 nM capsaicin and measured with an enzyme-linked immunosorbent assay (ELISA). ELISA results established that SP can be released locally from trigeminovascular system. The released SP was comparatively minor compared to the CGRP release from stimulated dura mater, trigeminal ganglion neurons and fibres. We hypothesize that SP and CGRP signalling pathways may work in tandem to exacerbate painful stimuli in the TGV system.

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Gleason, Neil R., George Gallos, Yi Zhang, and Charles W. Emala. "Propofol Preferentially Relaxes Neurokinin Receptor-2-induced Airway Smooth Muscle Contraction in Guinea Pig Trachea." Anesthesiology 112, no. 6 (June 1, 2010): 1335–44. http://dx.doi.org/10.1097/aln.0b013e3181d3d7f6.

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Background Propofol is the anesthetic of choice for patients with reactive airway disease and is thought to reduce intubation- or irritant-induced bronchoconstriction by decreasing the cholinergic component of vagal nerve activation. However, additional neurotransmitters, including neurokinins, play a role in irritant-induced bronchoconstriction. We questioned the mechanistic assumption that the clinically recognized protective effect of propofol against irritant-induced bronchoconstriction during intubation was due to attenuation of airway cholinergic reflexes. Methods Muscle force was continuously recorded from isolated guinea pig tracheal rings in organ baths. Rings were subjected to exogenous contractile agonists (acetylcholine, histamine, endothelin-1, substance P, acetyl-substance P, and neurokinin A) or to electrical field stimulation (EFS) to differentiate cholinergic or nonadrenergic, noncholinergic nerve-mediated contraction with or without cumulatively increasing concentrations of propofol, thiopental, etomidate, or ketamine. Results Propofol did not attenuate the cholinergic component of EFS-induced contraction at clinically relevant concentrations. In contrast, propofol relaxed nonadrenergic, noncholinergic-mediated EFS contraction at concentrations within the clinical range (20-100 mum, n = 9; P < 0.05), and propofol was more potent against an exogenous selective neurokinin-2 receptor versus neurokinin-1 receptor agonist contraction (n = 6, P < 0.001). Conclusions Propofol, at clinically relevant concentrations, relaxes airway smooth muscle contracted by nonadrenergic, noncholinergic-mediated EFS and exogenous neurokinins but not contractions elicited by the cholinergic component of EFS. These findings suggest that the mechanism of protective effects of propofol against irritant-induced bronchoconstriction involves attenuation of tachykinins released from nonadrenergic, noncholinergic nerves acting at neurokinin-2 receptors on airway smooth muscle.

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Ellis, James L. "Neurokinin receptors subserving bronchoconstriction." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 923–26. http://dx.doi.org/10.1139/y95-127.

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Tachykinin receptor subtypes were initially defined using agonist potency ratios for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB. On this basis it was suggested that there are three tachykinin receptor subtypes. These subtypes were designated NK1, NK2, and NK3, where SP is most potent at NK1 receptors, NKA is most potent at NK2 receptors, and NKB is most potent at NK3 receptors. Recently analogs of the endogenous ligands that show greater selectivity (about 1000-fold) for the different receptor subtypes have been developed. In addition selective antagonists, which are either nonpeptides or modified peptides, for the receptor subtypes have been developed. This minireview concentrates on the wealth of new knowledge concerning the tachykinin receptor subtypes subserving bronchoconstriction in several mammalian species, including man, provided by the use of these selective agonists and antagonists.Key words: neurokinins, bronchoconstriction, substance P, neurokinin A, receptor subtypes.

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Dornan, Wayne A., Krista L. Vink, Peter Malen, Kevin Short, William Struthers, and Christopher Barrett. "Site-specific effects of intracerebral injections of three neurokinins (neurokinin A, neurokinin K, and neurokinin γ) on the expression of male rat sexual behavior." Physiology & Behavior 54, no. 2 (August 1993): 249–58. http://dx.doi.org/10.1016/0031-9384(93)90107-q.

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8

Eistetter, H. R., D. J. Church, A. Mills, P. P. Godfrey, A. M. Capponi, R. Brewster, M. F. Schulz, E. Kawashima, and S. J. Arkinstall. "Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways." Cell Regulation 2, no. 10 (October 1991): 767–79. http://dx.doi.org/10.1091/mbc.2.10.767.

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Neurokinins are a family of neuropeptides with widespread distribution mediating a broad spectrum of physiological actions through three distinct receptor subtypes: NK-1, NK-2, and NK-3. We investigated some of the second messenger and cellular processes under control by the recombinant bovine NK-2 receptor stably expressed in Chinese hamster ovary cells. In this system the NK-2 receptor displays its expected pharmacological characteristics, and the physiological agonist neurokinin A stimulates several cellular responses. These include 1) transient inositol 1,4,5-trisphosphate (IP3) formation and Ca2+ mobilization, 2) increased out put of arachidonic acid and prostaglandin E2 (PGE2), 3) enhanced cyclic AMP (cAMP) generation, 4) increased de novo DNA synthesis, and 5) an induction of the "immediate early" genes c-fos and c-jun. Although NK-2 receptor-mediated IP3 formation involves activation of a pertussis toxin-insensitive G-protein, increased cAMP production is largely a secondary response and can be at least partially attributed to autocrine stimulation by endogenously generated eicosanoids, particularly PGE2. This is the first demonstration that a single recombinant neurokinin receptor subtype can regulate, either directly or indirectly, multiple signal transduction pathways and suggests several potential important mediators of neurokinin actions under physiological conditions.

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Koelbel, C. B., E. A. Mayer, J. R. Reeve, W. J. Snape, A. Patel, and F. J. Ho. "Involvement of substance P in noncholinergic excitation of rabbit colonic muscle." American Journal of Physiology-Gastrointestinal and Liver Physiology 256, no. 1 (January 1, 1989): G246—G253. http://dx.doi.org/10.1152/ajpgi.1989.256.1.g246.

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Neurokinins have been implicated as noncholinergic excitatory neurotransmitters in the mammalian gastrointestinal tract. To characterize the myogenic and neurogenic response of colonic muscle to neurokinins we studied the mechanical response of muscle strips from proximal and distal colon and the release of [3H]acetylcholine in response to substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). All neurokinins caused a dose-dependent inotropic response. SP was 80 times more potent in distal compared with proximal longitudinal muscle. The rank order of potencies in proximal longitudinal muscle was NKA greater than SP = NKB and in distal muscle NKA = SP = NKB. Desensitization to SP or pretreatment with a SP antagonist inhibited the mechanical response to SP and the atropine-resistant inotropic off response to electrical stimulation. Only longitudinal muscle from distal colon had an atropine- and hexamethonium-sensitive inotropic component to SP. In contrast, all three peptides were equipotent in releasing [3H]acetylcholine from longitudinal muscle strips preincubated with [3H]choline. These results suggest the following: 1) SP is a potent agonist of rabbit colon with a proximal distal gradient in biological potency; 2) the myogenic response of the distal colon appears to be mediated through a NK-1 receptor; and 3) SP is a major mediator of the noncholinergic component of the off response in distal longitudinal muscle.

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10

Canning, Brendan J., Sandra M. Reynolds, Linus U. Anukwu, Radhika Kajekar, and Allen C. Myers. "Endogenous neurokinins facilitate synaptic transmission in guinea pig airway parasympathetic ganglia." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, no. 2 (August 1, 2002): R320—R330. http://dx.doi.org/10.1152/ajpregu.00001.2002.

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Neurokinin-containing nerve fibers were localized to guinea pig airway parasympathetic ganglia in control tissues but not in tissues pretreated with capsaicin. The purpose of the present study was to determine whether neurokinins, released during axonal reflexes or after antidromic afferent nerve stimulation, modulate ganglionic synaptic neurotransmission. The neurokinin type 3 (NK3) receptor antagonists SB-223412 and SR-142801 inhibited vagally mediated cholinergic contractions of bronchi in vitro at stimulation voltages threshold for preganglionic nerve activation but had no effect on vagally mediated contractions evoked at optimal voltage or field stimulation-induced contractions. Intracellular recordings from the ganglia neurons revealed that capsaicin-sensitive nerve stimulation potentiated subsequent preganglionic nerve-evoked fast excitatory postsynaptic potentials. This effect was mimicked by the NK3 receptor agonist senktide analog and blocked by SB-223412. In situ, senktide analog markedly increased baseline tracheal cholinergic tone, an effect that was reversed by atropine and prevented by vagotomy or SB-223412. Comparable effects of intravenous senktide analog on pulmonary insufflation pressure were observed. These data highlight the important integrative role played by parasympathetic ganglia and indicate that activation of NK3 receptors in airway ganglia by endogenous neurokinins facilitates synaptic neurotransmission.

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Bannon, Michael J., and Christopher J. Whitty. "Neurokinin receptor gene expression in substantia nigra: localization, regulation, and potential physiological significance." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 866–70. http://dx.doi.org/10.1139/y95-119.

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Neurokinin receptor gene expression within the rat and human substantia nigra was examined in detail. In the rat, the relative abundances of nigral neurokinin receptor mRNAs were neurokinin 3 > neurokinin 1 [Formula: see text] neurokinin 2. High levels of neurokinin 3 mRNA were localized to dopamine neurons, as determined by dopamine cell lesions and colocalization with tyrosine hydroxylase mRNA. Stimulation of nigral neurokinin 3 receptors activated dopamine cells, as evidenced by increases in striatal dopamine metabolism and in a postsynaptic measure of dopamine neurotransmission (i.e., striatal substance P encoding mRNA). These and other anatomical and physiological data suggest that in the rat, substance P (released from striatonigral neurons) may act on nigral nondopamine cells through neurokinin 1 receptors, while the substance P cotransmitter neurokinin A may act preferentially on nigral dopamine neurons through neurokinin 3 receptors. Interestingly, high levels of neurokinin 1 (but not neurokinin 3) receptor mRNA are seen within human substantia nigra dopamine cells. Thus drugs interacting with neurokinin receptors may prove to be of value in the treatment of various neuropsychiatric disorders.Key words: neurokinin receptor, mRNA, dopamine, substantia nigra, human.

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Accili, Eric A., Alison M. J. Buchan, Yin Nam Kwok, John R. Ledsome, and John C. Brown. "Presence and actions of vasoactive intestinal peptide in the isolated rabbit heart." Canadian Journal of Physiology and Pharmacology 73, no. 1 (January 1, 1995): 134–39. http://dx.doi.org/10.1139/y95-019.

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The objectives of these experiments were to localize vasoactive intestinal peptide immunoreactivity (VIP-IR) in the intracardiac ganglia of the interatrial septum of the rabbit heart and to examine the effects of vasoactive intestinal peptide (VIP) on the isolated perfused rabbit heart. Cell bodies of neurones containing VIP-IR were located in the interatrial septa of rabbit hearts by using immunocytochemistry. In addition, the effects of substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) on the isolated rabbit heart were compared with those of VIP. Bolus injections of SP, NKA, VIP, and NKB caused dose-dependent decreases in the perfusion pressure of hearts perfused at constant flow with ED50 values of 2.73 ± 0.10 fmol (n = 6), 0.18 ± 0.01 pmol (n = 8), 93.75 ± 1.88 pmol (n = 6), and 75.00 ± 3.06 pmol (n = 6), respectively. The slope of the dose–response curve of VIP was much greater than those of SP and NKA, suggesting the presence of one receptor subtype for VIP and multiple receptor subtypes for the neurokinins on rabbit coronary vessels. Differences in the slopes of the dose–response curves and potency may reflect differences in the mechanism of vasodilatation. The maximal values of vasodilatation of all of the peptides did not differ. None of the peptides produced significant changes in heart rate, left ventricular pressure, or contractility. These results suggest that VIP found in the intracardiac neurones of the rabbit heart can mediate coronary vasodilatation.Key words: coronary vasodilatation, intracardiac ganglia, substance P, neurokinin A, neurokinin B.

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Hasséssian, Harout, Réjean Couture, and Line Jacques. "Spinal action of neurokinins in the rat: effects on mean arterial pressure, heart rate, and vascular permeability." Canadian Journal of Physiology and Pharmacology 65, no. 11 (November 1, 1987): 2182–87. http://dx.doi.org/10.1139/y87-344.

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In urethane-anaesthetized rats, the intrathecal administration of 6.5 nmol of substance P (SP), neurokinin A (NKA), or neurokinin B (NKB) at the T8–T10 level of the spinal cord enhances mean arterial pressure and heart rate. However, in the pentobarbital-anaesthetized rat, while NKB produces no effect on mean arterial pressure, NKA produces a biphasic change and SP, a depressor response. All three neurokinins elicit a tachycardia. The following rank order of potency SP ≥ NKA > NKB is observed in relation to these cardiovascular responses when either one of the two anaesthetics is used. The low cardiovascular activity of NKB cannot be attributed to its hydrophobicity, as the water soluble analogue of NKB, [Arg0] NKB, elicits a response as weak as the native peptide. In pentobarbital-anaesthetized rats, the intrathecal administration of 6.5 nmol of SP, also enhances plasma protein extravasation in cutaneous tissues of the back, the hind paws, and the ears. In this response NKA and NKB are either inactive (skin of hind paws) or less potent than SP (ears and dorsal skin). These findings agree with the hypothesis that in the rat spinal cord, the neurokinin receptor producing changes in mean arterial pressure, heart rate, and vascular permeability is of the NK-1 subtype.

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Eapen, Prasanth M., Chamallamudi Mallikarjuna Rao, and Madhavan Nampoothiri. "Crosstalk between neurokinin receptor signaling and neuroinflammation in neurological disorders." Reviews in the Neurosciences 30, no. 3 (April 24, 2019): 233–43. http://dx.doi.org/10.1515/revneuro-2018-0021.

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AbstractThe neurokinin 1 receptor with the natural substrate substance P is one of the intensely studied receptors among the neurokinin receptors. The intracellular signaling mechanism uses G protein-coupled transduction regulating various physiological processes from nausea to Alzheimer’s disease. The neurokinin 1 receptor plays a significant role in neuroinflammation-mediated alterations in neural circuitry. Neurokinin 1 receptor antagonists are selective, potent and exhibited efficacy in animal models of nervous system disorders. Evolving data now strengthen the viewpoint of brain substance P/neurokinin 1 receptor axis-mediated action in neural circuit dysfunction. Thus, a deep-rooted analysis of disease mechanism in which the neurokinin 1 receptor is involved is necessary for augmenting disease models which encourage the pharmaceutical industry to intensify the research pipeline. This review is an attempt to outline the concept of neurokinin 1 receptor signaling interlinked to the brain innate immune system. We also uncover the mechanisms of the neurokinin 1 receptor involved in neurological disorder and various methods of modulating the neurokinin 1 receptor, which may result in therapeutic action.

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REGOLI, D., K. NGUYEN, and G. CALÓ. "Neurokinin Receptors." Annals of the New York Academy of Sciences 812, no. 1 Receptor Clas (May 1997): 144–46. http://dx.doi.org/10.1111/j.1749-6632.1997.tb48155.x.

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Appell, Kenneth C., Thomas D. Y. Chung, Kelli J. Solly, and Daniel Chelsky. "Biological Characterization of Neurokinin Antagonists Discovered Through Screening of a Combinatorial Library." Journal of Biomolecular Screening 3, no. 1 (February 1998): 19–27. http://dx.doi.org/10.1177/108705719800300103.

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Recent advances in combinatorial chemistry have resulted in the rapid screening of libraries against biological targets. Another advance in biological screening is the ability to design and utilize novel, automated, nonradioactive assays for targets of pharmaceutical interest. Using encoding technology and europium time-resolved fluorescence, we have designed primary receptor binding assays to define active compounds against the neurokinin-1 and neurokinin-2 receptor subtypes. In addition, a secondary, cell-based, functional assay measuring intracellular calcium flux with calcium sensitive fluorophores was used to determine receptor agonist or antagonist activities. We adapted a cuvette based assay to a CCD camera and digital imaging system that allowed us to demonstrate functional receptor antagonist activity in all 96 wells of a microtiter plate simultaneously. The screening of a 20,000 member library using europium labeled neurokinin ligands resulted in the identification of 43 active compounds for neurokinin-1 and 27 for neurokinin-2. Through medicinal chemistry and structure-activity relationships, a compound was synthesized with balanced dual antagonist activity at both neurokinin receptors with greater than 100-fold less activity against the neurokinin-3 receptor subtype. The structure-activity relationships generated from this initial library can now be used to design a new focused library to improve on neurokinin-1/neurokinin-2 receptor potency and selectivity.

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Koelbel, C. B., E. A. Mayer, G. van Deventer, W. J. Snape, and A. Patel. "Characterization of the effects of neurokinins on canine antral muscle." American Journal of Physiology-Gastrointestinal and Liver Physiology 255, no. 6 (December 1, 1988): G779—G786. http://dx.doi.org/10.1152/ajpgi.1988.255.6.g779.

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The excitation of longitudinal antral muscle by substance P (SP) involves both a myogenic and a cholinergic effect. To examine if these responses are mediated by different neurokinin receptors, we studied the mechanical response and the release of [3H]acetylcholine from antral muscle strips in response to SP, substance P methylester (SPME), neurokinin A (NKA), neurokinin B (NKB), and several non-mammalian tachykinins. All peptides studied showed a dose-dependent inotropic and chronotropic effect on spontaneous phasic contractions. This ionotropic effect in longitudinal muscle was partially atropine sensitive for SPME, SP, and NKB but not for NKA, whereas neither atropine nor tetrodotoxin had an effect in circular muscle. In longitudinal muscle, all three neurokinins were equipotent. In longitudinal muscle treated with atropine and in circular muscle, the rank order of potency for the inotropic response was NKA greater than NKB greater than SP greater than SPME. For the chronotropic response the rank order was SPME, SP greater than NKA greater than NKB. NKA, NKB, and SP caused a dose-dependent, tetrodotoxin-sensitive increase in [3H]acetylcholine release from strips preincubated with [3H]choline. NKA was significantly more potent to release [3H]acetylcholine than either NKB or SP. The stimulated release was inhibited by [D-Ala2,D-Met5]methionine enkephalinamide and the SP antagonist, spantide. These results are consistent with the hypothesis that NKA is the natural ligand mediating the myogenic inotropic response in both muscle layers and the cholinergic response in longitudinal muscle.

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Mayer, E. A., C. B. Koelbel, W. J. Snape, G. Vandeventer, and L. Leduc. "Neurokinin inhibition of cholinergic myenteric neurons in canine antrum." American Journal of Physiology-Gastrointestinal and Liver Physiology 258, no. 1 (January 1, 1990): G122—G128. http://dx.doi.org/10.1152/ajpgi.1990.258.1.g122.

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Neurokinins regulate gastrointestinal motility by interacting with receptors on both muscle layers and on myenteric plexus neurons. To determine if specific neurokinin (NK) receptor agonists can mediate inhibitory effects on myenteric neurons, we studied the effect of the NK-1 agonist substance P methylester (SPME) and the putative endogenous NK-2 receptor ligand neurokinin A (NKA) on [3H]acetylcholine [( 3H]ACh) release induced by electrical field stimulation from muscle strips cut from the canine gastric antrum. SPME but not NKA caused a dose-dependent inhibition of stimulated [3H]ACh release in tissues containing the myenteric plexus. The inhibition was not seen in longitudinal muscle without myenteric plexus. Pretreatment of tissues with indomethacin or antiserum to vasoactive intestinal polypeptide (VIP) but not naloxone or adrenergic or cholingergic blockade abolished the SPME-induced inhibition. Exogenous VIP stimulated the release of prostaglandin E2 (PGE2) from full thickness strips, and both VIP and PGE2 inhibited [3H]ACh release induced by electrical depolarization. These findings suggest that NK-1 receptor agonists can selectively inhibit stimulated [3H]ACh release and that this inhibition may involve the release of VIP and PGE2 from neurons within the myenteric plexus.

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Vannucchi, Maria Giuliana, and Stefano Evangelista. "Neurokinin receptors in the gastrointestinal muscle wall: cell distribution and possible roles." BioMolecular Concepts 4, no. 3 (June 1, 2013): 221–31. http://dx.doi.org/10.1515/bmc-2013-0001.

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AbstractThe neurokinin receptors are G-protein-linked receptors; three distinct molecules, called neurokinin-1, neurokinin-2, and neurokinin-3 receptors, have been identified. Their physiological ligands are the tachykinins, which, in the mammalian gut, correspond to substance P, neurokinin A, and neurokinin B. In this apparatus, the main source of tachykinins is represented by intrinsic neurons located either in the myenteric plexus and projecting mainly to the muscle coat, or in the submucous plexus and projecting to the mucosa and submucosal blood vessels. The availability of specific antibodies has allowed identifying the sites of distribution of the neurokinin receptors in the gut, and important differences have been found among cell types and animal species. The complexity of the receptor distribution, either intraspecies or interspecies, is in agreement with the variegated picture coming out from physiological and pharmacological experiments. Interestingly, most of the knowledge on the tachykinin systems has been obtained from pathological conditions. Here, we tried to collect the main information available on the cellular distribution of the neurokinin receptors in the gut wall in the attempt to correlate their cell location with the several roles the tachykinins seem to play in the gastrointestinal apparatus.

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Dion, S., N. Rouissi, F. Nantel, D. Jukic, N. E. Rhaleb, C. Tousignant, S. Télémaque, et al. "Structure-Activity Study of Neurokinins: Antagonists for the Neurokinin-2 Receptor." Pharmacology 41, no. 4 (1990): 184–94. http://dx.doi.org/10.1159/000138717.

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Schmid, Eduard, Johannes Leierer, Gerhard Kieselbach, Barbara Teuchner, Martina Kralinger, Reiner Fischer-Colbrie, James E. Krause, et al. "Neurokinin A and neurokinin B in the human retina." Peptides 27, no. 12 (December 2006): 3370–76. http://dx.doi.org/10.1016/j.peptides.2006.07.021.

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Li, Yuting, Jiying Zhang, Louis D. Falo, Adriana T. Larregina, and Tina L. Sumpter. "The pseudo-allergy receptor, MrgprB2/X2 is controlled by neurokinin A and the neurokinin 2 receptor in human and mouse skin." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 66.17. http://dx.doi.org/10.4049/jimmunol.204.supp.66.17.

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Abstract Within the skin, mast cells (MCs) and sensory neurons form a cohesive unit that plays an important role in initiating immune responses. Neuropeptides such as neurokinin A and substance P direct MC function by initiating signaling through neurokinin (NK) receptors, and Mas related G-protein receptors (Mrgpr)s. Neurokinin A, in particular, is thought to signal through the NK2R. Recent studies highlight the importance of the MrgprB2 (mouse) and MrgprX2 (human) in the MC response to pseudo-allergens, secretagogues and substance P. To date, a relationship between neurokinin receptors and the MrgprB2/X2 has not been investigated. In this study, we hypothesize that MrgprB2/X2 expression is controlled by the NK2R and its high affinity ligand, neurokinin A. In mice, we show that administration of neurokinin A diminishes MrgprB2 expression. Surprisingly, antagonism of the NK2R also downregulates MrgprB2 expression and in NK2R-deficient mice, MrgprB2 expression is markedly diminished. In contrast, co-administration of neurokinin A and a NK2R antagonist markedly increases MrgprB2 expression. In human skin explants, NK2R antagonism has minimal effect on MrgprX2 expression, but co-administration of neurokinin A and a NK2R antagonist upregulates MrgprX2 expression, as seen in murine skin. These data demonstrate that NK2R-signaling influences MrgprB2/X2 expression and, in absence of the NK2R, neurokinin A interacts with an unknown receptor to increase MrpgrB2/X2 expression. Collectively, these data uncover a novel role for NK2R signaling in the regulation of MrgprB2/X2. These important findings have implications for patients with dysregulated mast cell function initiated through the MrgprX2.

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Gembitsky, Dmitry S., Sándor Lovas, and Richard F. Murphy. "Development of a High Throughput Functional Assay for Structure-Activity Studies of Neurokinin A Analogs." Journal of Biomolecular Screening 3, no. 3 (April 1998): 183–88. http://dx.doi.org/10.1177/108705719800300304.

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A great variety of functional assays are in use to evaluate novel ligands of tachykinin receptors. These techniques, however, are generally labor and time consuming and hardly suitable for high throughput screening. Using human recombinant NK-2 receptors expressed in CHO cells, we have developed an assay based on direct measurement of guanine nucleotide exchange on G-proteins. [35S]GTPγS, which cannot be hydrolyzed by the intrinsic GTPase activity of the α-subunit of heterotrimeric G-protein, was employed. Six ligands of NK-2 receptors including both natural neurokinins and neurokinin A analogs were used for the assay validation. The assay was shown to discriminate successfully between partial and full agonism, as well as between agonism and antagonism of the peptides. Besides the exquisite specificity and high throughput, the assay obviates the need for laboratory animals and cumbersome muscle-bath techniques for conventional tachykinin pharmacology. The functional GTPγS assay is a specific and reliable high throughput screening tool for the investigation of pharmacologic properties of neurokinin A analogs. The assay has multiple advantages over existing techniques and is favored for studies on structure-activity relationships in peptides.

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Zhou, Yu, Meng Wang, Yingna Tong, Xiaobin Liu, Lufang Zhang, Dong Dong, Jie Shao, and Yunli Zhou. "miR-206 Promotes Cancer Progression by Targeting Full-Length Neurokinin-1 Receptor in Breast Cancer." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381987516. http://dx.doi.org/10.1177/1533033819875168.

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Substance P plays a pivotal role in human cancer development and progression by binding to its receptor, neurokinin-1. Neurokinin-1 has 2 isoforms: full-length neurokinin-1 and truncated neurokinin-1, the latter lacking the cytoplasmic terminal 96-amino acid residues of the full-length protein. We have identified 3 candidate miR-206 target sites within the 3′-untranslated region of the full-length neurokinin-1 gene from bioinformatics database searches. In the present study, real-time quantitative polymerase chain reaction was performed to quantify the expression of miR-206, and the expression of neurokinin-1 and full-length neurokinin-1 was detected by immunohistochemistry in 82 clinical cases of breast cancer and paired adjacent normal tissues. The miR-206 target gene was demonstrated by using a dual-luciferase reporter assay, quantitative real-time polymerase chain reaction, and Western blotting. Transwell migration and invasion, colony formation, and proliferation assays were performed to evaluate the effects of miR-206 expression on various aspects of breast cancer cell behavior in vitro. We showed that miR-206 expression is upregulated in breast cancer cell lines and breast cancer tissues when compared to that in adjacent normal tissues, and full-length neurokinin-1 expression inversely correlates with Tumor Lymph Node Metastasis (TNM) stage and lymph node metastasis. Western blotting, quantitative real-time polymerase chain reaction, and dual-luciferase reporter assays demonstrated that miR-206 binds the 3′-untranslated region of full-length neurokinin-1 messenger RNA, regulating protein expression. We showed that the overexpression of miR-206 promotes breast cancer cell invasion, migration, proliferation, and colony formation in vitro. The present study furthers the current understanding of the mechanisms underlying breast cancer pathogenesis and may be useful for the development of novel targeted therapies.

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Meuchel, Lucas W., Alecia Stewart, Dan F. Smelter, Amard J. Abcejo, Michael A. Thompson, Syed I. A. Zaidi, Richard J. Martin, and Y. S. Prakash. "Neurokinin-neurotrophin interactions in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 1 (July 2011): L91—L98. http://dx.doi.org/10.1152/ajplung.00320.2010.

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Neurally derived tachykinins such as substance P (SP) play a key role in modulating airway contractility (especially with inflammation). Separately, the neurotrophin brain-derived neurotrophic factor (BDNF; potentially derived from nerves as well as airway smooth muscle; ASM) and its tropomyosin-related kinase receptor, TrkB, are involved in enhanced airway contractility. In this study, we hypothesized that neurokinins and neurotrophins are linked in enhancing intracellular Ca2+ concentration ([Ca2+]i) regulation in ASM. In rat ASM cells, 24 h exposure to 10 nM SP significantly increased BDNF and TrkB expression ( P < 0.05). Furthermore, [Ca2+]i responses to 1 μM ACh as well as BDNF (30 min) effects on [Ca2+]i regulation were enhanced by prior SP exposure, largely via increased Ca2+ influx ( P < 0.05). The enhancing effect of SP on BDNF signaling was blunted by the neurokinin-2 receptor antagonist MEN-10376 (1 μM, P < 0.05) to a greater extent than the neurokinin-1 receptor antagonist RP-67580 (5 nM). Chelation of extracellular BDNF (chimeric TrkB-Fc; 1 μg/ml), as well as tyrosine kinase inhibition (100 nM K252a), substantially blunted SP effects ( P < 0.05). Overnight (24 h) exposure of ASM cells to 50% oxygen increased BDNF and TrkB expression and potentiated both SP- and BDNF-induced enhancement of [Ca2+]i ( P < 0.05). These results suggest a novel interaction between SP and BDNF in regulating agonist-induced [Ca2+]i regulation in ASM. The autocrine mechanism we present here represents a new area in the development of bronchoconstrictive reflex response and airway hyperreactive disorders.

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Sakurada, Tsukasa, Chikai Sakurada, Koichi Tan-No, and Kensuke Kisara. "Neurokinin Receptor Antagonists." CNS Drugs 8, no. 6 (December 1997): 436–47. http://dx.doi.org/10.2165/00023210-199708060-00002.

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27

Elliott, Jason, and Eileen M. Seward. "Neurokinin receptor antagonists." Expert Opinion on Therapeutic Patents 7, no. 1 (January 1997): 43–54. http://dx.doi.org/10.1517/13543776.7.1.43.

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Seward, Eileen M., and Christopher J. Swain. "Neurokinin receptor antagonists." Expert Opinion on Therapeutic Patents 9, no. 5 (May 1999): 571–82. http://dx.doi.org/10.1517/13543776.9.5.571.

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29

Regoli, D., and R. Couture. "Neurokinin receptor antagonists." Neuropeptides 24, no. 4 (April 1993): 232–33. http://dx.doi.org/10.1016/0143-4179(93)90242-3.

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Leroy, Vincent, Peter Mauser, Zhongli Gao, and Norton P. Peet. "Neurokinin receptor antagonists." Expert Opinion on Investigational Drugs 9, no. 4 (April 2000): 735–46. http://dx.doi.org/10.1517/13543784.9.4.735.

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Ganjiwale, Anjali D., Gita Subbarao, and Sudha M. Cowsik. "Molecular Modeling of Neurokinin B and Neurokinin-3 Receptor Complex." Biophysical Journal 100, no. 3 (February 2011): 178a—179a. http://dx.doi.org/10.1016/j.bpj.2010.12.1195.

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32

Lévesque, Martin, Marie-Josée Wallman, Remy Parent, Attila Sík, and André Parent. "Neurokinin-1 and neurokinin-3 receptors in primate substantia nigra." Neuroscience Research 57, no. 3 (March 2007): 362–71. http://dx.doi.org/10.1016/j.neures.2006.11.002.

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33

Wang, Y., T. Badgery-Parker, S. Lovas, N. Chartrel, H. Vaudry, E. Burcher, and J. M. Conlon. "Primary structure and receptor-binding properties of a neurokinin A-related peptide from frog gut." Biochemical Journal 287, no. 3 (November 1, 1992): 827–32. http://dx.doi.org/10.1042/bj2870827.

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A tachykinin peptide was isolated from an extract of the intestine of the European green frog, Rana ridibunda, and its primary structure was established as: His-Lys-Leu-Asp-Ser-Phe-Ile-Gly-Leu-Met.CONH2. This sequence was confirmed by chemical synthesis and shows two amino acid substitutions (leucine for threonine at position 3 and isoleucine for valine at position 7) compared with neurokinin A. Binding parameters for synthetic [Leu3, Ile7]neurokinin A and mammalian tachykinins were compared using receptor-selective radioligands and crude membranes from tissues enriched in the NK1, NK2 and NK3 receptors. [Leu3, Ile7]Neurokinin A was approx. 3-fold less potent than substance P in inhibiting the binding of 125I-labelled [Sar9, Met(O2)11]substance P (labelled with Bolton-Hunter reagent) to rat submandibular gland (NK1 receptor), 8-fold less potent than neurokinin A in inhibiting the binding of [2-[125I]iodohistidine1]neurokinin A to rat stomach fundus (NK2 receptor) and 6-fold less potent than neurokinin B in inhibiting the binding of 125I-Bolton-Hunter-labelled scyliorhinin II to rat brain (NK3 receptor). Thus the frog neurokinin A-related peptide shows moderate affinity but lack of selectivity for all three tachykinin-binding sites in rat tissues. This non-selectivity is similar to that displayed by the molluscan tachykinin, eledoisin, which also contains an isoleucine residue in the corresponding position in the molecule.

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Steinhoff, Martin S., Bengt von Mentzer, Pierangelo Geppetti, Charalabos Pothoulakis, and Nigel W. Bunnett. "Tachykinins and Their Receptors: Contributions to Physiological Control and the Mechanisms of Disease." Physiological Reviews 94, no. 1 (January 2014): 265–301. http://dx.doi.org/10.1152/physrev.00031.2013.

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The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists.

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Gao, X. P., R. A. Robbins, R. M. Snider, J. Lowe, S. I. Rennard, P. Anding, and I. Rubinstein. "NK1 receptors mediate tachykinin-induced increase in microvascular clearance in hamster cheek pouch." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 2 (August 1, 1993): H593—H598. http://dx.doi.org/10.1152/ajpheart.1993.265.2.h593.

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The purpose of this study was to determine the receptor subtype(s) that mediates tachykinin-induced neurogenic plasma extravasation in the hamster cheek pouch. Changes in microvascular clearance were quantified by counting the number of leaky sites and calculating the clearance of fluorescein isothiocyanate-dextran [mol wt 70,000 (Dextran 70)] during suffusion of the cheek pouch with substance P, neurokinin A, neurokinin B, and capsaicin. Suffusion of substance P, capsaicin, and neurokinin A, but not neurokinin B, was associated with a significant concentration-dependent increase in leaky site formation and clearance of fluorescein isothiocyanate-Dextran 70 (P < 0.05). However, the responses to substance P and capsaicin were significantly greater than those to neurokinin A. Pretreatment with the selective, nonpeptide NK1 receptor antagonist, CP-96,345, significantly attenuated substance P- and capsaicin-induced but not neurokinin A-induced responses (P < 0.05). These effects were specific, since the 2R,3R enantiomer, CP-96,344, was inactive, and CP-96,345 had no significant effect on adenosine-induced responses. We conclude that, in the hamster cheek pouch, NK1 receptors are the predominant receptors that mediate neurogenic plasma extravasation.

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36

Lemay, François, Chakib Ameziane Hassani, and André G. Michel. "Structural requirements for molecular recognition by the Neurokinin receptors." Canadian Journal of Chemistry 68, no. 7 (July 1, 1990): 1186–91. http://dx.doi.org/10.1139/v90-183.

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Populations of lower energy conformers have been generated by conformational energy calculations, using empirical energy functions, for the C-terminal pentapeptide of Substance P (CH3-CO-Phe-Phe-Gly-Leu-Met-NH2), Neurokinins A and B (CH3-CO-Phe-Val-Gly-Leu-Met-NH2), and Eledoisin (CH3-CO-Phe-Ile-Gly-Leu-Met-NH2). The C-terminal sequences are greatly conserved in the Neurokinin and Tachychinin families of peptides and are mainly responsible for the molecular recognition. These sequences differ in the nature of the second residue. This substitution interferes with the recognition processes and modulates the specificities. A procedure based on a random generation of conformers, followed by energy minimizations, has been applied to produce the populations of conformers for the three pentapeptides. The conformational properties of the lower energy conformers have been analysed and compared with respect to the substitution of the second residue. Earlier nuclear magnetic resonance data as well as structure–activity relationship results have been interpreted in light of the proposed stable conformers. It is shown that the selectivity towards the NK3 receptor requires a structure with a restrained flexibility introduced at the second N-terminal residue. The selectivity towards the NK1 receptor is shown to be related to the presence of a constrained structure at the Gly residue. These structures suggest further chemical modifications be introduced in order to produce more selective and stable analogues. Keywords: peptide conformation, empirical energy, Neurokinin, molecular recognition.

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37

Sculptoreanu, Adrian, and William C. de Groat. "Protein Kinase C Is Involved in Neurokinin Receptor Modulation of N- and L-Type Ca2+ Channels in DRG Neurons of the Adult Rat." Journal of Neurophysiology 90, no. 1 (July 2003): 21–31. http://dx.doi.org/10.1152/jn.00108.2003.

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Whole cell patch-clamp techniques were used to examine neurokinin receptor modulation of Ca2+ channels in small to medium size dorsal root ganglia neurons (<40 pF) that express mainly N- and L-type Ca2+ currents. Low concentrations of substance P enhanced Ca2+ currents (5–40%, <0.2 μM), while higher concentrations applied cumulatively reversed these enhancements (5–28% reductions, >0.5 μM). This apparent inhibition by high concentrations of substance P was blocked by the administration of the NK3 antagonist SB 235,375 (0.2 μM). The NK1 agonist, [Sar9,Met11]-substance P (0.05 to 1.0 μM) did not alter Ca2+ currents; whereas the NK2 agonist, [βAla8]-neurokinin A (4–10), enhanced Ca2+ currents (5–36% increase, 0.05–0.5 μM). The enhancement was reversed by the NK2 antagonist MEN 10,376 (0.2 μM) but unaffected by the NK3 antagonist SB 235,375 (0.2 μM). The NK3 agonist [MePhe7]-neurokinin B (0.5–1.0 μM) inhibited Ca2+ currents (6–24% decrease). This inhibition was not prevented by the NK2 antagonist MEN 10,376 (0.2 μM) but was blocked by the NK3 antagonist SB 235,375 (0.2 μM). Both the enhancement and inhibition of Ca2+ currents by neurokinin agonists were reversed by the protein kinase C inhibitor bisindolylmaleimide I HCl (0.2–0.5 μM). Following inhibition of Ca2+ channels by [MePhe7]-neurokinin the facilitatory effect of BayK 8644 (5 μM) was increased and the inhibitory effect of the N-type Ca2+ channel blocker w -conotoxin GVIA (1 μM) was diminished, suggesting that the NK3 agonist inhibits N-type Ca2+ channels. Similarly, block of all but N-type Ca2+ channels, revealed that [βAla8]-neurokinin A (4–10) enhanced the currents while [MePhe7]-neurokinin B inhibited the currents. Inhibition of all but L-type Ca2+ channels, revealed that [βAla8]-neurokinin A (4–10) enhanced the currents while [MePhe7]-neurokinin B had no effect. Activation of protein kinase C with low concentrations of phorbol-12,13-dibutyrate enhanced Ca2+ currents, but high concentrations inhibited N- and L-type Ca2+ currents. In summary, these data suggest that in adult rat dorsal root ganglia neurons, NK2 receptors enhance both L- and N-type Ca2+ channels and NK3 receptors inhibit N-type Ca2+ channels and that these effects are mediated by protein kinase C phosphorylation of Ca2+ channels.

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38

Hooper, N. M., A. J. Kenny, and A. J. Turner. "The metabolism of neuropeptides. Neurokinin A (substance K) is a substrate for endopeptidase-24.11 but not for peptidyl dipeptidase A (angiotensin-converting enzyme)." Biochemical Journal 231, no. 2 (October 15, 1985): 357–61. http://dx.doi.org/10.1042/bj2310357.

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Both endopeptidase-24.11 and peptidyl dipeptidase A have previously been shown to hydrolyse the neuropeptide substance P. The structurally related peptide neurokinin A is also shown to be hydrolysed by pig kidney endopeptidase-24.11. The identified products indicated hydrolysis at two sites, Ser5-Phe6 and Gly8-Leu9, consistent with the known specificity of the enzyme. The pattern of hydrolysis of neurokinin A by synaptic membranes prepared from pig striatum was similar to that observed with purified endopeptidase-24.11, and hydrolysis was substantially abolished by the selective inhibitor phosphoramidon. Peptidyl dipeptidase A purified from pig kidney was shown to hydrolyse substance P but not neurokinin A. It is concluded that endopeptidase-24.11 has the general capacity to hydrolyse and inactivate the family of tachykinin peptides, including substance P and neurokinin A.

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39

Mastrangelo, D., R. Mathison, H. J. Huggel, S. Dion, P. D'Orléans-Juste, N. E. Rhaleb, G. Drapeau, P. Rovero, and D. Regoli. "The rat isolated portal vein: a preparation sensitive to neurokinins, particularly neurokinin B." European Journal of Pharmacology 134, no. 3 (February 1987): 321–26. http://dx.doi.org/10.1016/0014-2999(87)90363-3.

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40

Jensen, J., K. R. Olson, and J. M. Conlon. "Primary structures and effects on gastrointestinal motility of tachykinins from the rainbow trout." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 265, no. 4 (October 1, 1993): R804—R810. http://dx.doi.org/10.1152/ajpregu.1993.265.4.r804.

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Purification and structural characterization of tachykinins from rainbow trout (Oncorhynchus mykiss) intestine has demonstrated the presence of three different peptides related to the mammalian tachykinins: substance P, neurokinin A, and neuropeptide-gamma. The substance P- and the neurokinin A-related peptides present in the intestine are identical to the tachykinins previously isolated from the trout brain. The neuropeptide-gamma-related peptide (Ser-Ser-Ala-Asn-Pro-Gln-Ile-Thr-Arg-Lys-Arg-His-Lys-Ile-Asn-Ser-Phe- Val-Gly-Leu-Met-NH2), not previously identified in brain tissue, has the sequence of the neurokinin A-related tachykinin at its COOH-terminus. Both trout substance P and neurokinin A stimulated the motility of isolated trout intestinal muscle [pD2(-log of EC50) values 8.5 +/- 0.15 and 7.35 +/- 0.08, respectively] and the vascularly perfused trout stomach (pD2 values 9.63 +/- 0.23 and 8.18 +/- 0.23, respectively). Trout substance P was 14 times more potent than trout neurokinin A in the intestine and 28 times more potent in the stomach. The data suggest that receptors interacting with tachykinins in the trout gastrointestinal tract have a similar selectivity as the mammalian NK-1 receptor.

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41

Gadais, Charlène, and Steven Ballet. "The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications." Current Medicinal Chemistry 27, no. 9 (March 27, 2020): 1515–61. http://dx.doi.org/10.2174/0929867325666180913095918.

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The neurokinins are indisputably essential neurotransmitters in numerous pathoand physiological events. Being widely distributed in the Central Nervous System (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. As a necessity for molecular tools to understand the biological role of this class, endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference to small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately were combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.

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42

Giardina, Giuseppe AM, and Luca F. Raveglia. "Neurokinin-3 receptor antagonists." Expert Opinion on Therapeutic Patents 7, no. 4 (April 1997): 307–23. http://dx.doi.org/10.1517/13543776.7.4.307.

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QUIRION, RÉMI, THAN-VINH DAM, and STEVE GUARD. "Selective Neurokinin Receptor Radioligands." Annals of the New York Academy of Sciences 632, no. 1 Substance P a (September 1991): 137–44. http://dx.doi.org/10.1111/j.1749-6632.1991.tb33102.x.

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44

REGOLI, D., F. NANTEL, C. TOUSIGNANT, D. JUKIC, N. ROUISSI, N.-E. RHALEB, S. TÉLÉMAQUE, G. DRAPEAU, and P. D'ORLÉANS-JUSTE. "Neurokinin Agonists and Antagonists." Annals of the New York Academy of Sciences 632, no. 1 Substance P a (September 1991): 170–83. http://dx.doi.org/10.1111/j.1749-6632.1991.tb33105.x.

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45

Eisuke, Munekata. "Neurokinin A and B." Comparative Biochemistry and Physiology Part C: Comparative Pharmacology 98, no. 1 (January 1991): 171–79. http://dx.doi.org/10.1016/0742-8413(91)90193-w.

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46

Takaya, T. "Discovery of neurokinin antagonists." Pure and Applied Chemistry 68, no. 4 (January 1, 1996): 875–80. http://dx.doi.org/10.1351/pac199668040875.

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47

Regoli, D., and F. Nantel. "Pharmacology of neurokinin receptors." Biopolymers 31, no. 6 (May 1991): 777–83. http://dx.doi.org/10.1002/bip.360310623.

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48

de Croft, Simon, Ulrich Boehm, and Allan E. Herbison. "Neurokinin B Activates Arcuate Kisspeptin Neurons Through Multiple Tachykinin Receptors in the Male Mouse." Endocrinology 154, no. 8 (August 1, 2013): 2750–60. http://dx.doi.org/10.1210/en.2013-1231.

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Abstract Kisspeptin neurons located in the arcuate nucleus (ARN) coexpress dynorphin and neurokinin B (NKB) and may interact to influence gonadotropin secretion. Using a kisspeptin-green fluorescent protein mouse model, the present study examined whether the neuropeptides kisspeptin, dynorphin, and NKB modulate the electrical activity of ARN kisspeptin neurons in the adult male mouse. Cell-attached recordings showed that kisspeptin itself had no effect on kisspeptin neuron firing. Dynorphin and the κ-opioid receptor agonist U50-488 evoked a potent suppression of all ARN kisspeptin neuron firing that was blocked completely by the κ-opioid receptor antagonist nor-Binaltorphimine. Both NKB and Senktide, a neurokinin 3 receptor agonist, exerted a potent stimulatory action on ∼95% of ARN kisspeptin neurons. Although the selective neurokinin 3 receptor antagonists SB222200 and SR142801 blocked the effects of Senktide on kisspeptin neurons, they surprisingly had no effect on NKB activation of firing. Studies with selective neurokinin 1 receptor (SDZ-NKT343) and neurokinin 2 receptor (GR94800) antagonists revealed that the activation of kisspeptin neurons by NKB was only blocked completely by a cocktail of antagonists against all 3 tachykinin receptors. Whole-cell recordings revealed that individual kisspeptin neurons were activated directly by all 3 tachykinins substance, P, neurokinin A, and NKB. These experiments show that dynorphin and NKB have opposing actions on the electrical activity of kisspeptin neurons supporting the existence of an interconnected network of kisspeptin neurons in the ARN. However, the effects of NKB result from an unexpected activation of multiple tachykinin receptors.

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King, Tamara E., and Gordon A. Barr. "Functional development of neurokinin peptides substance P and neurokinin A in nociception." NeuroReport 14, no. 12 (August 2003): 1603–7. http://dx.doi.org/10.1097/00001756-200308260-00012.

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Greenfeder, Scott, Boonlert Cheewatrakoolpong, Motasim Billah, Robert W. Egan, Elizabeth Keene, Nicholas J. Murgolo, and John C. Anthes. "The neurokinin-1 and neurokinin-2 receptor binding sites of MDL103,392 differ." Bioorganic & Medicinal Chemistry 7, no. 12 (December 1999): 2867–76. http://dx.doi.org/10.1016/s0968-0896(99)00220-5.

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Journal articles on the topic 'Neurokinin'

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