IN-VITRO AND IN-VIVO BIOLOGICAL-ACTIVITIES OF SR140333, A NOVEL POTENT NONPEPTIDE TACHYKININ NK1, RECEPTOR ANTAGONIST

-3-yl)ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vi tro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar(9),Met(O-2)(11)]substance P-induced endothelium-dependen t relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 mu M, it had no effect in bioassays for NK2 ([beta Ala( 8)]neurokinin A-induced contraction of endothelium-deprived rabbit pul monary artery) and NK3 ([MePhe(7)]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK, receptors was apparently non-competitive, with pD(2)(') values (an tagonism potency evaluated by the negative logarithm of the molar conc entration of antagonist that produces a 50% reduction of the maximal r esponse to the agonist) between 9.65 and 10.16 in the different assays . SR140333 also blocked in vitro [Sar(9),Met(O-2)(11)]substance P-indu ced release of acetylcholine from rat striatum. In vivo, SR140333 exer ted highly potent antagonism toward [Sar(9),Met(O-2)(11)]substance P-i nduced hypotension in dogs (ED(50) = 3 mu g/kg i.v.), bronchoconstrict ion in guinea-pig (ED(50) = 42 mu g/kg i.v.) and plasma extravasation in rats (ED(50) = 7 mu g/kg i.v.). Finally, it also blocked the activa tion of rat thalamic neurons after nociceptive stimulation (ED(50) = 0 .2 mu g/kg i.v.).