Pharmacological profile of a new potent and specific ?2-adrenoceptor antagonist, L-657,743

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Abstract
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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