ANTIBRONCHOSPASTIC ACTIVITY OF MEN10,627, A NOVEL TACHYKININ NK2 RECEPTOR ANTAGONIST, IN GUINEA-PIG AIRWAYS

The antibronchospastic activity against acetylcholine, antigen, histam ine plus platelet-activating factor (PAF) or the selective tachykinin neurokinin (NK)(1) and NK2 receptor agonists of the novel tachykinin N K2 receptor antagonist, MEN10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo (2 beta-5 beta)), was studied in anesthetized guinea-pigs. MEN10,627 ( 30-100 nmol/kg i.v.) reduced in a dose-dependent manner the bronchospa sm induced by the tachykinin NK2 receptor agonist [beta Ala(8)]neuroki nin A-(4-10) and the effect of the highest dose lasted up to 5 h from its administration. Conversely, airway constriction induced by the NK1 receptor agonist [Sar(9)]substance P sulfone or acetylcholine was una ffected by MEN10,627 up to a dose of 3 mu mol/kg i.v. In animals sensi tized with ovalbumin and pretreated with the endopeptidase inhibitor p hosphoramidon, the aerosolized antigen produced a bronchospasm which w as inhibited by MEN10,627 (30-100 nmol/kg i.v.) but not by the tachyki nin NK1 receptor antagonist, (+/-)-CP96,345 ([2R,3R-cis- and phenyl)-m ethyl]-1-azabicyclo[2.2.2]octan-3-amine]) (3 mu mol/kg i.v.). Both MEN 10,627 (30-100 nmol/kg i.v.) and (+/-)-CP96,345 (30-300 nmol/kg i.v.) reduced the PAF-induced hyperresponsiveness to histamine, without affe cting the hypotension induced by PAF or the bronchospasm induced by hi stamine in guinea-pigs not exposed to PAF, showing the involvement of both tachykinin NK1 and NK2 receptors in this model. In summary, MEN10 ,627 behaves as a potent, selective and long-lasting tachykinin NK2 re ceptor antagonist in vivo. Further, tachykinin NK2 receptors could be activated during allergic responses and in the development of airway h yperresponsiveness.