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

Abstract (R)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)-ethyl]-4-phenylpiperidin-4-yl}-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK 2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK 2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK 2 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 (ID 50 = 21 μg kg −1 i.v. and 250 μg kg −1 i.d.) and [βAla 8 ]neurokinin A-(4–10)-induced urinary bladder contraction in rats (ID 50 = 11 μg kg −1 i.v. and 190 μg 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 μg 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 (ID 50 = 3 μg kg −1 i.v. and 16 μg kg −1 p.o.).