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L-654,284 a new potent and selective α2-adrenoceptor antagonist

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Summary

L-654,284 ((2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizine-2-yl)-N-methyl-2-hydroxyethanesulfonamide) was tested in several in vitro and in vivo models for α2-adrenoceptor antagonist activity and compared to several reference agents. In vitro L-654,284 competed for the binding of 3H-clonidine or 3H-rauwolscine (K i's 0.8 nM, 1.1 nM) and blocked the presynaptic effects of clonidine in the rat isolated vas deferens (pA2, 9.1). L-654,284 exhibited marked α2- vs. α1-adrenoceptor selectivity in vitro, inhibiting 3H-prazosin binding with a K i of 110 nM and blocking the effects of methoxamine on the vas deferens with a pA2 of 7.5. In vivo L-654,284 at 22 nmoles/kg i.v. doubled the ED50 of clonidine to produce mydriasis in rats. Given orally, the potency of L-654,284 in this test was reduced by a factor of 5.5. L-654,284 also potently increased cerebrocortical NE turnover in the rat, another in vivo index of α2-adrenoceptor blockade in the central nervous system. In the periphery, L-654,284 demonstrated α2-adrenoceptor selectivity by preferentially blocking the pressor effects of UK 14304 versus those of methoxamine in the pithed rat. Overall, L-654,284 was generally a more potent α2-adrenoceptor antagonist than RX 781094 with comparable α2/α1 selectivity and was several times more potent and α2-selective than WY 26703 or yohimbine. In addition, L-654,284 had better (5–6 times) oral bioavailability than RX 781094 or WY 26703.

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Author notes

  1. G. E. Martin

    Present address: Department of Biological Research, McNeil Pharmaceuticals, 19477, Spring House, PA, USA

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 & G. E. Martin

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

    J. R. Huff, W. C. Randall, J. Vacca & J. J. Baldwin

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. G. E. Martin
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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. J. J. Baldwin
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Pettibone, D.J., Clineschmidt, B.V., Lotti, V.J. et al. L-654,284 a new potent and selective α2-adrenoceptor antagonist. Naunyn-Schmiedeberg's Arch. Pharmacol. 333, 110–116 (1986). https://doi.org/10.1007/BF00506512

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  • DOI: https://doi.org/10.1007/BF00506512

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