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

L-657,743,(2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12 b-octahydro-2H- benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one, was tested in several in vitro and in vivo models for alpha 2-adrenoceptor antagonism. L-657,743 exhibited a high affinity (less than or equal to 1 nM) for alpha 2-adrenoceptors labelled by [3H] rauwolscine or [3H]clonidine with a 240-fold selectivity versus alpha 1-adrenoceptors labelled by [3H]prazosin. L-657,743 was a potent, selective, and competitive alpha 2-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 alpha 2-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 alpha 2-specificity versus other monoamine receptor mechanisms. Compared to yohimbine, L-657,743 had considerably higher alpha 2-antagonist potency and alpha 2/alpha 1 selectivity and was significantly more alpha 2-specific (i.e., vs. DA, 5-HT receptors).