2-Phenyl-4-quinolinecarboxamides: A Novel Class of Potent and Selective Non-Peptide Competitive Antagonists for the Human Neurokinin-3 Receptor

Autor: Dulcie B. Schmidt, Andrew D. Medhurst, Marco Vassallo, Mario Grugni, Douglas W. P. Hay, Giuseppe Giardina, Carlo Farina, Henry M. Sarau, Vittorio Vecchietti, Roberto Rigolio, James J. Foley, Luca F. Raveglia
Rok vydání: 1996
Předmět:
Zdroj: Journal of Medicinal Chemistry. 39:2281-2284
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm9602423
Popis: Pharmacological and molecular biological studies indicate the existence of at least three human tachykinin receptor subtypes, designated neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3),1-3 which belong to the superfamily of G-protein-coupled receptors possessing seven transmembrane domains.4 The endogenous ligands for these receptors constitute a family of small neuropeptides, named tachykinins or neurokinins, which share the common carboxy-terminal region Phe-X-Gly-Leu-MetNH2. The main mammalian tachykinins, substance P, neurokinin A (NKA), and neurokinin B (NKB), interact with all three tachykinin receptors, although there is a defined agonist rank order of potency for NK-1, NK-2, and NK-3 receptors, respectively; for example, for the NK-3 receptor the rank potency order is NKB > NKA > substance P. Over the past few years potent and selective peptide and non-peptide antagonists for the NK-1 and NK-2 receptors have been identified.5-8 These pharmacological tools accelerated the clarification of physiological and pathophysiological roles of these receptors9 and the potential therapeutic indications for NK-1 and NK-2 receptor antagonists.10-13 In contrast to the NK-1 and NK-2 receptor research area, there is limited information on the biology and potential pathophysiological significance of the NK-3 receptor. This was, to a large extent, due to the lack of sufficient potency and selectivity of the peptide NK-3 antagonists described thus far14 and to the absence of non-peptide NK-3 receptor ligands until recently. However, the recent disclosure of the “peptoid” NK-3 antagonist PD 15767215 and the peptidederived PD 16118216 has provided improved reagents for these studies and stimulated the search for more potent and metabolically stable non-peptide NK-3 receptor antagonists. The human NK-3 (hNK-3) receptor mRNA has been detected, using polymerase chain reaction (PCR), to various regions in the central nervous system (CNS) and also, albeit to a lesser extent, in some peripheral tissues, including kidney, placenta, lung, and colon.17 Activation of NK-3 receptors modulates the release of various transmitters in the CNS and periphery,18-20 suggesting that they may have a neuromodulatory role. Recently, (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl}-4-phenylpiperidin-4-yl}-Nmethylacetamide, SR 142801 (1, Chart 1), was reported as the first potent non-peptide NK-3 receptor antagonist.21,22 Chemically, SR 142801 derives from a constrained analog of SR 48968, a potent NK-2 receptor antagonist (Ki ) 0.51 nM, for displacement of [125I]NKA) in rat duodenum membranes,7 which has moderate affinity for NK-3 receptors (IC50 ) 320 nM, for displacement of [3H]senktide {succinyl-[Asp9MePhe8]SP(6-13)}) in guinea pig cerebral cortex membranes.23 We now report on the discovery of a novel class of potent and selective non-peptide NK-3 receptor antagonistssstructurally unrelated to the piperidine derivatives SR 142801 and SR 48968swhich are based on the 2-phenylquinoline backbone.24 Chemical synthesis (Scheme 1), radioligand binding affinities for the cloned human neurokinin receptors stably expressed in CHO cell lines (hNKs-CHO),17,25,26 in vitro functional activity in the rabbit isolated iris sphincter muscle preparation (antagonism of senktide-induced contraction),27 and structure-activity relationships (SARs) of the novel † Italy. ‡ USA. § England. © Copyright 1996 by the American Chemical Society
Databáze: OpenAIRE
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