Non‐Peptide Oxytocin Agonists.

Pitt, Gary R. W.; Batt, Andrzej R.; Haigh, R. M.; Penson, Andrew M.; Robson, Peter A.; Rooker, David P.; Tartar, André; Trim, Julie E.; Yea, Christopher; Roe, Michael B.

doi:10.1002/chin.200452146

Cited by 13 publications

(31 citation statements)

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“…This explains why typical vasopressin receptor antagonists are very hydrophobic 115, 116. Due to the high similarity between vasopressin and oxytocin receptors, it is difficult to find selective nonpeptide agonists for these receptors, especially for the oxytocin receptor (only moderately selective oxytocin receptor agonists have been described yet) 117. Fine subtype selectivity for antagonists is easier to tackle and may be regulated by single amino acid differences at the receptor level (e.g., positions 5.42 and 7.39 for vasopressin V 1a and V 1b receptors) 114.…”

Section: Resultsmentioning

confidence: 99%

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

et al. 2005

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The amino acid sequences of 369 human nonolfactory G-protein-coupled receptors (GPCRs) have been aligned at the seven transmembrane domain (TM) and used to extract the nature of 30 critical residues supposed--from the X-ray structure of bovine rhodopsin bound to retinal--to line the TM binding cavity of ground-state receptors. Interestingly, the clustering of human GPCRs from these 30 residues mirrors the recently described phylogenetic tree of full-sequence human GPCRs (Fredriksson et al., Mol Pharmacol 2003;63:1256-1272) with few exceptions. A TM cavity could be found for all investigated GPCRs with physicochemical properties matching that of their cognate ligands. The current approach allows a very fast comparison of most human GPCRs from the focused perspective of the predicted TM cavity and permits to easily detect key residues that drive ligand selectivity or promiscuity.

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Section: Resultsmentioning

confidence: 99%

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

et al. 2005

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“…8B) and selective V 1a receptor antagonists including the orally active relcovaptan (Fig. 8C) available [340][341][342]. These drugs represent important tools to further define the involvement of oxytocin and vasopressin receptors in epilepsy by means of their usage in animal experimentation.…”

Section: Oxytocin and Vasopressinmentioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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“…Correspondingly, several nonpeptide oxytocin agonists or oxytocin antagonists have a central therapeutic relevance: antagonist L‐371,257 (CAS# 162042–44‐6) (K i = 9.3 nM) [117,118]—which does not cross the blood brain barrier when administered in the CNS [119], L‐368,899 (antagonist, CAS# 148927–60‐0, CNS effects after oral administration, see Refs. 120,121), WAY‐162,720 ([119], which is a brain‐penetrant oxytocin receptor antagonist when administered peripherally), WAY‐267,464 (agonist, which has been successfully introduced as an anxiolytic in mice, see [122], US patent assigned to Wyeth Corp, [50,123]) and Compound 27 (agonist, EC 50 = 33 nM, 25 times more selective over vasopressin receptors, [124]). Compound 27 has been classified in the list of drugs putatively having a central effect, but this should be taken carefully since its biological actions are still under investigation.…”

Section: Pharmacology Of Oxytocin Agonists and Antagonistsmentioning

confidence: 99%

REVIEW: Oxytocin: Crossing the Bridge between Basic Science and Pharmacotherapy

Viero

Shibuya

Naoki

et al. 2010

CNS Neuroscience & Therapeutics

230

183

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Is oxytocin the hormone of happiness? Probably not. However, this small nine amino acid peptide is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress, which makes oxytocin and its receptor potential candidates as targets for drug therapy. In this review, we address the issues of drug design and specificity and focus our discussion on recent findings on oxytocin and its heterotrimeric G protein-coupled receptor OTR. In this regard, we will highlight the following topics: (i) the role of oxytocin in behavior and affectivity, (ii) the relationship between oxytocin and stress with emphasis on the hypothalamo–pituitary–adrenal axis, (iii) the involvement of oxytocin in pain regulation and nociception, (iv) the specific action mechanisms of oxytocin on intracellular Ca2+ in the hypothalamo neurohypophysial system (HNS) cell bodies, (v) newly generated transgenic rats tagged by a visible fluorescent protein to study the physiology of vasopressin and oxytocin, and (vi) the action of the neurohypophysial hormone outside the central nervous system, including the myometrium, heart and peripheral nervous system. As a short nine amino acid peptide, closely related to its partner peptide vasopressin, oxytocin appears to be ideal for the design of agonists and antagonists of its receptor. In addition, not only the hormone itself and its binding to OTR, but also its synthesis, storage and release can be endogenously and exogenously regulated to counteract pathophysiological states. Understanding the fundamental physiopharmacology of the effects of oxytocin is an important and necessary approach for developing a potential pharmacotherapy.

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Non‐Peptide Oxytocin Agonists.

Abstract: Non-Peptide Oxytocin Agonists. -Compound (XI) shows strong oxytocin-receptor binding activity. -(PITT, G. R. W.; BATT, A. R.; HAIGH, R. M.; PENSON, A. M.; ROBSON, P. A.; ROOKER, D. P.; TARTAR, A. L.; TRIM, J. E.; YEA, C. M.; ROE*, M. B.; Bioorg. Med.

Cited by 13 publications

References 1 publication

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

REVIEW: Oxytocin: Crossing the Bridge between Basic Science and Pharmacotherapy

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