Alpha 2-adrenoceptor antagonist potencies of two hydroxylated metabolites of yohimbine.

1. The alpha 2-adrenoceptor antagonist capacities of two hydroxylated metabolites of yohimbine in man (10-OH-yohimbine and 11-OH-yohimbine) were investigated on the alpha 2-adrenoceptors of human platelets and adipocytes and compared to those of yohimbine. 2. Yohimbine and 11-OH-yohimbine exhibited similar alpha 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 [3H]-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 alpha 2-adrenoceptor antagonist properties. The discrepancies found in binding studies (i.e. 10 fold lower affinity of 11-OH-yohimbine than yohimbine for alpha 2-adrenoceptors but similar capacities in blocking biological alpha 2-adrenoceptor effects in cells) are attributable to the higher degree of binding of yohimbine to plasma protein.