WAY 100289: Pharmacological profile of a novel 5‐HT3 receptor antagonist

Abstract

AbstractWAY 100289, endo‐N‐[8‐methyl‐8‐azabicyclo [3.2.1.] octan‐3‐yl) aminocarbonyl]‐2‐cyclopropylmethoxybenzamide, was an antagonist of 5‐HT evoked depolarization (5‐HT3 receptor‐mediated) of the rat isolated cervical vagus nerve (pA2 value 8.9). Schild‐plot analysis was consistent with a competitive antagonist mechanism (slope 0.8), though antagonism was not fully surmountable. WAY 100289 was a relatively weak antagonist of 5‐HT3 receptor‐mediated contractions of the guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus preparation (pA2 value 6.2). In 5‐HT3 receptor binding studies in rat entorhinal cortex membranes WAY 100289 displaced [3H]‐zacopride with a pK1 value of 8.4, in good agreement with results in the vagus nerve. In urethane anaesthetised rats the 5‐HT evoked Bezold‐Jarisch reflex was blocked by WAY 100289 with an ED50 of 1.3 μg/kg i.v., consistent with 5‐HT3 receptor antagonism. In the conscious rat WAY 100289 was approximately 30‐fold more potent by the i.v. than by the p.o. route. Following a dose of 1 mg/kg of WAY 100289 the Bezold‐Jarisch reflex was reduced by more than 50% for in excess of 6 h. In a series of in vitro functional and ligand binding assays WAY 100289 showed good selectivity for the 5‐HT3 receptor with the only notable additional activity that of non‐competitive antagonism of nicotinic receptor mediated depolarization of the rat vagus nerve (−log IC50 value 6.7). The compound was without significant effect as an inhibitor of the uptake of 5‐hydroxytryptamine, noradrenaline or dopamine by rat brain synaptasomes. In general, WAY 100289 is a novel, achiral 5‐HT3 receptor antagonist with good in vitro potency and selectivity and good in vivo activity, oral bio‐availability, and duration of action. © 1993 Wiley‐Liss, Inc.