BRL-46470A - A HIGHLY POTENT, SELECTIVE AND LONG-ACTING 5-HT(3) RECEPTOR ANTAGONIST WITH ANXIOLYTIC-LIKE PROPERTIES

The novel 5-HT3 antagonist, BRL 46470A (endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)2,3-dihydro-3,3 dimethyl-indole-1-carboxamide, hydrochloride), has been investigated in a series of in vitro and in vivo tests, including the effect of the drug in models of anxiolysis. In classical tests for 5-HT3 receptor antagonism, BRL 46470A was shown to antagonise 5-HT3 mediated responses in the guinea-pig ileum [pA2 8.3 +/- 0.5, slope 0.98 +/- 0.20, mean +/- SEM (5)], the rabbit isolated heart (pA2 10.1 +/- 0.1, slope 1.2 +/- 0.2, n = 5) and the rat Bezold-Jarisch model (ID50 0.7 mug/kg IV +/- 0.1, n = 8), with a long duration of action (> 3 h). BRL 46470A selectively displaced [H-3]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (K(i) 0.32 nM +/- 0.04, n = 4) without displacing (at concentrations greater than 1 muM) a wide variety of ligands binding to other neurotransmitter receptors, opioid receptors and to neurotransmitter gated ion channel complexes. In vivo, BRL 46470A showed anxiolytic-like activity in two animal models predictive of antianxiety effects-elevated X-maze and social interaction in rats. In both models, BRL 46470A showed significant activity over a wide dose-range following both oral (0.0001-0.1 mg/kg PO) and systemic administration. The unique level of potency of BRL 46470A was apparent in the rat social interaction test and was shown to be 100 fold more potent than the 5-HT3 receptor antagonist ondansetron, with no evidence of a bell-shaped dose response curve over 4 orders of magnitude. BRL 46470A (0.0001 and 0.01 mg/kg SC) also reduced the anxiogenic effects of m-CPP (1-(3-chlorophenyl) piperazine) in the rat elevated X-maze. BRL 46470A is therefore a chemically novel potent and selective 5-HT3 receptor antagonist with anxiolytic potential and a long duration of action in animal studies.