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BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties

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Abstract

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 µg/kg IV±0.1,n=8), with a long duration of action (>3 h). BRL 46470A selectively displaced [3H]-BRL 43694 from 5-HT3 binding sites in rat brain membranes (Ki 0.32 nM±0.04,n=4) without displacing (at concentrations greater than 1 µM) 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.

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Authors and Affiliations

  1. SmithKline Beecham Pharmaceuticals, Coldharbour Road, The Pinnacles, CM19 5AD, Harlow, Essex, UK

    T. P. Blackburn, G. S. Baxter, G. A. Kennett, F. D. King, D. C. Piper, G. J. Sanger, D. R. Thomas, N. Upton & M. D. Wood

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  1. T. P. Blackburn
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  2. G. S. Baxter
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  3. G. A. Kennett
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  4. F. D. King
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  5. D. C. Piper
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  6. G. J. Sanger
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  7. D. R. Thomas
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  8. N. Upton
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  9. M. D. Wood
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Blackburn, T.P., Baxter, G.S., Kennett, G.A. et al. BRL 46470A: a highly potent, selective and long acting 5-HT3 receptor antagonist with anxiolytic-like properties. Psychopharmacology 110, 257–264 (1993). https://doi.org/10.1007/BF02251279

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  • DOI: https://doi.org/10.1007/BF02251279

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