189815-82-5Relevant articles and documents
Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 1. Identification of the 4-quinolinecarboxamide framework
Giardina, Giuseppe A. M.,Sarau, Henry M.,Farina, Carlo,Medhurst, Andrew D.,Grugni, Mario,Raveglia, Luca F.,Schmidt, Dulcie B.,Rigolio, Roberto,Luttmann, Mark,Vecchietti, Vittorio,Hay, Douglas W. P.
, p. 1794 - 1807 (1997)
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 33-76, prompted by chemical modifications of the prototype 4, 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 (65, SB 218795, hNK-3-CHO binding K(i) = 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 65 is about 90-fold selective for hNK-3 versus hNK-2 receptors (hNK-2-CHO binding K(i) = 1221 nM) and over 7000-fold selective versus hNK-1 receptors (hNK-1-CHO binding K(i) = >100 μM). In vitro functional studies in rabbit isolated iris sphincter muscle preparation demonstrated that 65 is a competitive antagonist of the contractile response induced by the potent and selective NK-3 receptor agonist senktide with a K(b) = 43 nM. Overall, the data indicate that 65 is a potent and selective hNK-3 receptor antagonist and a useful lead for further chemical optimization.
