SR120819A, AN ORALLY-ACTIVE AND SELECTIVE NEUROPEPTIDE-Y Y1 RECEPTOR ANTAGONIST

An orally-active antagonist of neuropeptide Y (NPY) Y-1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (K-i = 15 mM) NPY Y-1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y-1 agonist, [Leu(31),Pro(34)]NPY, on rabbit vas deferens contraction (pA(2) = 7.20 +/- 0.07). In vivo, by intravenous route, this compound acts as an antagonist in anesthetized guinea-pigs and, notably, after oral administration, SR 120819A counteracts the presser response of [Leu(31),Pro(34)]NPY (5 mu g/kg i.v.) with a long duration of action (> 4 h at 5 mg/kg p.o.). Thus, SR 120819A is the first orally-effective NPY Y-1 receptor antagonist yet described, It could be a useful tool for exploring the role of NPY and the therapeutic relevance of an antagonist at NPY Y-1 receptors.