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

WAY 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.