Discovery of a Novel Class of Selective Non-Peptide Antagonists for the Human Neurokinin-3 Receptor. 1. Identification of the 4-Quinolinecarboxamide Framework

A novel class of potent and selective non-peptide neurokinin-3 (NK-3) receptor antagonists, featuring the 4-quinolinecarboxamide framework, has been designed based upon chemically diverse NK-1 receptor antagonists. The novel compounds <BO>33</BO>−<BO>76</BO>, prompted by chemical modifications of the prototype <BO>4</BO>, have been characterized by binding analysis using a membrane preparation of chinese hamster ovary (CHO) cells expressing the human neurokinin-3 receptors (hNK-3-CHO), and clear structure−activity relationships (SARs) have been established. From SARs, (R)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (<BO>65</BO>, SB 218795, hNK-3-CHO binding K<INF>i</INF> = 13 nM) emerged as one of the most potent compounds of this novel class. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that <BO>65</BO> is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding K<INF>i</INF> = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding K<INF>i</INF> = >100 μM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that <BO>65</BO> is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a K<INF>b</INF> = 43 nM. Overall, the data indicate that <BO>65</BO> is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization.