NOVEL SELECTIVE AND PARTIAL AGONISTS OF 5-HT3 RECEPTORS .1. SYNTHESISAND BIOLOGICAL EVALUATION OF PIPERAZINOPYRROLOTHIENOPYRAZINES

A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazin e derivatives were prepared and evaluated in order to determine the ne cessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitution s on the piperazine and the thiophene ring of the pyrrolothienopyrazin e moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanom olar range of affinity for 5-HT3 receptors with high to very high sele ctivity (up to 10 000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b ) have been evaluated on the Von Bezold-Jarisch reflex and were charac terized as partial agonists. One of them, 13a, has shown in vivo at ve ry low dose a potent anxiolytic-like activity in the light/dark test.