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

DJ Pettibone, BV Clineschmidt, VJ Lotti… - Naunyn-Schmiedeberg's …, 1987 - Springer
DJ Pettibone, BV Clineschmidt, VJ Lotti, JJ Baldwin, JR Huff, WC Randall, J Vacca…
Naunyn-Schmiedeberg's archives of pharmacology, 1987Springer
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 α 2-adrenoceptor antagonism. L-657,743 exhibited a high affinity
(⩽ 1 nM) for α 2-adrenoceptors labelled by [3 H] rauwolscine or [3H] clonidine with a 240-
fold selectivity versus α 1-adrenoceptors labelled by [3 H] prazosin. L-657,743 was a potent,
selective, and competitive α 2-adrenoceptor antagonist in the rat isolated vas deferens (pA …
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 α21 selectivity and was significantly more α2-specific (i.e., vs. DA, 5-HT receptors).
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