Pharmacological profile of a new potent and specific alpha 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-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).
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| Authors | D J Pettibone, B V Clineschmidt, V J Lotti, J J Baldwin, J R Huff, W C Randall, J Vacca, S D Young |
| Journal | Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 336 Issue 2 Pg. 169-75 (Aug 1987) ISSN: 0028-1298 [Print] Germany |
| PMID | 2891039 (Publication Type: Journal Article) |
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