Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist

(R)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)-ethyl]-4-phenylpiperidin-4-yl}-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA(2) values) between 9.08 and 10.10. In vivo, SR 144190 blocked [Nle(10)]neurokinin A-(4-10)-induced bronchoconstriction in guinea pigs (ID50 = 21 mu g kg(-1) i.v. and 250 mu g kg(-1) i.d.) and [beta Ala(8)]neurokinin A-(4-10)-induced urinary bladder contraction in rats (ID50 = 11 mu g kg(-1) i.v. and 190 mu g kg(-1) i.d.). It prevented citric acid-induced cough and airway hyperresponsiveness to acetylcholine in guinea pigs (1 mg kg(-1) i.p.) as well as castor oil-induced diarrhoea in rats (0.01-10 mu g kg(-1) s.c. or p.o). Finally, it blocked the turning behaviour induced by intrastriatal injections of [Nle(10)]neurokinin A-(4-10) in mice (ID50 = 3 mu g kg(-1) i.v. and 16 mu g kg(-1) p.o.).