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Pharmacological profile of a new potent and specific α2-adrenoceptor antagonist, L-657,743

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Summary

L-657,743, (2S,12bS)1′,3′-dimethylspiro (1, 3,4,5′, 6,6′, 7,12 b-octahydro-2-H-benzo[b]furo[2,3-a]quinolizine)-2, 4′- pyrimidin-2′-one, was tested in several in vitro and in vivo models for α2-adrenoceptor antagonism. L-657,743 exhibited a high affinity (⩽ 1 nM) for α2-adrenoceptors labelled by [3H] rauwolscine or [3H]clonidine with a 240-fold selectivity versus α1-adrenoceptors labelled by [3H]prazosin. L-657,743 was a potent, selective, and competitive α2-adrenoceptor antagonist in the rat isolated vas deferens (pA2 = 9.3 vs clonidine; pA2 = 7.1 vs methoxamine). In vivo, L-657,743 potently blocked clonidine-induced mydriasis in the rat and stimulated cerebrocortical norepinephrine synthesis, two indices of central α2-adrenoceptor antagonism. L-657,743 exhibited a comparatively low affinity for several monoamine receptor subtypes (D1, D2, 5-HT1, 5-HT2) in radioligand binding assays in vitro and a comparatively low potency to alter the synthesis of brain DA and 5-HT in vivo indicating a marked α2-specificity versus other monoamine receptor mechanisms. Compared to yohimbine, L-657,743 had considerably higher α2-antagonist potency and α2/α1 selectivity and was significantly more α2-specific (i.e., vs. DA, 5-HT receptors).

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Authors and Affiliations

  1. Department of Microbial Pharmacometrics, Merck, Sharp and Dohme Research Laboratories, 19486, West Point, PA, USA

    D. J. Pettibone, B. V. Clineschmidt & V. J. Lotti

  2. Medicinal Chemistry, Merck, Sharp and Dohme Research Laboratories, 19486, West Point, PA, USA

    J. J. Baldwin, J. R. Huff, W. C. Randall, J. Vacca & S. D. Young

Authors
  1. D. J. Pettibone
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  2. B. V. Clineschmidt
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  3. V. J. Lotti
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  4. J. J. Baldwin
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  5. J. R. Huff
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  6. W. C. Randall
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  7. J. Vacca
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  8. S. D. Young
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Pettibone, D.J., Clineschmidt, B.V., Lotti, V.J. et al. Pharmacological profile of a new potent and specific α2-adrenoceptor antagonist, L-657,743. Naunyn-Schmiedeberg's Arch Pharmacol 336, 169–175 (1987). https://doi.org/10.1007/BF00165801

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  • DOI: https://doi.org/10.1007/BF00165801

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