GR159897, A POTENT NONPEPTIDE ANTAGONIST AT TACHYKININ NK2 RECEPTORS

GR159897 )-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-methoxy-4- [(phenylsu lfinyl)methyl]piperidine) is a novel, highly potent and selective non- peptide antagonist at tachykinin NK2 receptors. GR159897 inhibited bin ding of the NK2 receptor antagonist radioligand [H-3]cyclohexylcarbony l-Gly-Ala-(D)Trp-Phe-NMe, ([H-3]GR100679) to human ileum NK2 receptors transfected into Chinese hamster ovary cells (pK(i) 9.5) and to rat c olon membranes (pK(i) 10.0). GR159897 was a competitive antagonist of contractions induced by the NK2 receptor agonist [Lys(3),Gly(8)-R-gamm a-lactam-Leu(9)]neurokinin A-(3-10) (GR64349) in guinea-pig trachea (p A(2) 8.7), and had negligible activity at human NK1 receptors transfec ted into Chinese hamster ovary cells (pK(i) 5.3), NK1 receptors in gui nea-pig trachea (pK(B) < 5) or NK3 receptors in guinea-pig cerebral co rtex (pK(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). GR 159897 should be a useful tool for studying the physiological and path ophysiological role of tachykinin Mt, receptor activation.