GR159897, a potent non-peptide antagonist at tachykinin NK 2 receptors

Abstract

GR159897 (( R)-1-[2-(5-fluoro-1 H-indol-3-yl)ethyl]-4-methoxy-4-[(phenylsulfinyl)methyl]piperidine) is a novel, highly potent and selective non-peptide antagonist at tachykinin NK 2 receptors. GR159897 inhibited binding of the NK 2 receptor antagonist radioligand [ 3H]cyclohexylcarbonyl-Gly-Ala-( d)Trp-Phe-NMe 2 ([ 3H]GR100679) to human ileum NK 2 receptors transfected into Chinese hamster ovary cells (p K i 9.5) and to rat colon membranes (p K i 10.0). GR159897 was a competitive antagonist of contractions induced by the NK 2 receptor agonist [Lys 3,Gly 8-R-γ-lactam-Leu 9]neurokinin A-(3–10) (GR64349) in guinea-pig trachea (pA 2 8.7), and had negligible activity at human NK 1 receptors transfected into Chinese hamster ovary cells (p K i 5.3), NK 1 receptors in guinea-pig trachea (p K B < 5) or NK 3 receptors in guinea-pig cerebral cortex (p K i < 5). In vivo, in the anaesthetised guinea-pig, GR159897 (0.12 mg · kg −1 i.v.) potently antagonised bronchoconstriction induced by GR64349 (dose-ratio = 28), with a long duration of action (3 h). GR159897 should be a useful tool for studying the physiological and pathophysiological role of tachykinin NK 2 receptor activation.