Potency and selectivity of the tachykinin NK3 receptor antagonist SR 142801

Binding studies indicated that tachykinin NK3 binding sites in peripheral (ileum) and central (cerebral cortex) tissues of the guinea pig exhibit similar pharmacological properties. They also confirmed that the tachykinin NK3 receptor antagonist (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4- yl)-N-methyl acetamide (SR 142801) has a higher affinity for tachykinin NK3 binding sites in the guinea pig than in the rat. SR 142801 exhibited a much lower affinity for tachykinin NK2 and NK1 binding sites. SR 142801 was shown to be a potent uncompetitive antagonist of the senktide-induced formation of [H-3]inositol monophosphate in slices from the guinea-pig ileum (apparent K-B = 3.2 nM, 51% reduction of the maximal response), a functional test for tachykinin NK3 receptors. In agreement with results of binding studies, the effect of SR 142801 Nas stereoselective since its enantiomer SR 142806 was much less potent. In the rat urinary bladder, a tissue devoid of tachykinin NK3 receptors, SR 142801 was without effect on the [Pro(9)]substance beta- or the septide-induced formation of [H-3]inositol monophosphate but it slightly reduced the response of the tachykinin NK2 receptor agonist [Lys(5),MeLeu(9),Nle(10)]neurokinin A-(4-10) (K-B = 339 nM). Altogether, these data indicate that SR 142801 is a highly selective tachykinin NK3 receptor antagonist which is more potent in the guinea pig than in the rat.