α 2 ‐Adrenoceptor antagonist potencies of two hydroxylated metabolites of yohimbine

1 The α 2 ‐adrenoceptor antagonist capacities of two hydroxylated metabolites of yohimbine in man (10‐OH‐yohimbine and 11‐OH‐yohimbine) were investigated on the α 2 ‐adrenoceptors of human platelets and adipocytes and compared to those of yohimbine. 2 Yohimbine and 11‐OH‐yohimbine exhibited similar α 2 ‐adrenoceptor affinity in biological studies i.e. inhibition of adrenaline‐induced platelet aggregation and inhibition of UK14304‐induced antilipolysis in adipocytes. 3 Yohimbine and the two metabolites displaced [ 3 H]‐RX 821002 binding with equivalent affinities in platelet and adipocyte membranes with the following order of potency: yohimbine > 11‐OH‐yohimbine > 10‐OH‐yohimbine. However, when binding studies were carried out in binding buffer supplemented with 5% albumin, the apparent affinity of yohimbine was reduced about 10 fold and was similar to that of 11‐OH‐yohimbine. 4 Yohimbine and its metabolites were bound to different extents to plasma proteins, the bound fraction being 82%, 43% and 32% respectively for yohimbine, 11‐OH‐yohimbine and 10‐OH‐yohimbine. 5 These results show that the main hydroxylated metabolite of yohimbine in man (11‐OH‐yohimbine) possesses α 2 ‐adrenoceptor antagonist properties. The discrepancies found in binding studies (i.e. 10 fold lower affinity of 11‐OH‐yohimbine than yohimbine for α 2 ‐adrenoceptors but similar capacities in blocking biological α 2 ‐adrenoceptor effects in cells) are attributable to the higher degree of binding of yohimbine to plasma protein.