Structure-Activity Relationship of Yohimbine and Its Related Analogs in Blocking Alpha-1 and Alpha-2 Adrenoceptors: A Comparative Study of Cardiovascular Activities

Abstract

We investigated the selectivities and structure requirements for alpha-1 and alpha-2 adrenoceptor blocking activities of yohimbine (YO) and its 12 related analogs, such as 0-yohimbine (0-YO), dihydrocorynantheine (DHC) and (—)indoloquinolizidine ((—)IQ). The affinity of YO analogs to alpha-adrenoceptor was assessed by measuring their blockade of pressor responses to epinephrine in pithed rats. Among YO structure groups, the potency order was YO> DHC = 0-YO >geissoschizine methylether > 140-hydroxy YO> 140-benzoyloxy YO (inactive). (—)IQ was slightly less potent than YO, but much stronger than (+)IQ. Among (±)IQ structure groups, the potency order was (±)IQ > (±)l,12b-trans-l-hydroxy IQ »(±)l,12b-cis-l' -hydroxy IQ (inactive). (+)Borrerine was active, but (+)des-methylborrerine was inactive. The alpha-1 blocking activities of the four compounds YO, 0-YO, DHC and (—)IQ, were assessed in experiments of pressor responses to methoxamine in pithed rats and contractile responses to methoxamine in the rat vas deferens. The potency order was (—)IQ > YO > DHC > 0-YO. Furthermore, the alpha-2 blocking activities of the four analogs were assessed in experiments of pressor responses to clonidine and inhibition of electrically driven cardioacceleration by clonidine, in pithed rats. The potency order was YO > 0-YO >(—)IQ> DHC. Based on the potency ratio between alpha-1 and alpha-2 blocking activities, DHC or YO was most selective for alpha-1 or alpha-2 subtype, respectively, among the four YO analogs. These results suggest that the A, B, C and D rings of YO analogs and their planarity are necessary for the affinity to alpha-adrenoceptors and that the predominant conformation of the carboxymethyl or hydroxy group on the E ring of YO structure determines the selectivity for alpha-1 and alpha-2 blocking activities. © 1990, The Pharmaceutical Society of Japan. All rights reserved.