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.
Berlan
M
M
INSERM U.317 Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, Toulouse, France.
Le Verge
R
R
Galitzky
J
J
Le Corre
P
P
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D000068438:Brimonidine Tartrate; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D019329:Idazoxan / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D011810:Quinoxalines / Q000494:pharmacology; D015016:Yohimbine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001798:Blood Proteins; D004146:Dioxanes; D011810:Quinoxalines; C081038:11-hydroxyyohimbine; D015016:Yohimbine; C081037:10-hydroxyyohimbine; D000068438:Brimonidine Tartrate; C058525:2-methoxyidazoxan; D019329:Idazoxan; D004837:Epinephrine