Mivazerol, a novel compound with high specificity for α2 adrenergic receptors: Binding studies on different human and rat membrane preparations

Abstract

Mivazerol, 3-[1(H-imidazol-4-yl)methyl]-2-hydroxybenzamide hydrochloride, a new potential anti-ischemic drug designed by UCB S.A. Pharma Sector, has been studied in binding experiments on adrenergic, dopaminergic, serotoninergic, muscarinic and idazoxan binding sites. Our results indicate that this compound displays high affinity and marked specificity for α 2 adrenoceptors. Mivazerol displaced the binding of the α 2 adrenoceptor antagonist [ 3H]RX 821002 to the α 2A adrenoceptors in human frontal cortex membranes with an apparent K i value of 37 nM. The competition curve was shallow ( n H = 0.55), suggesting that this compound acts as an α 2 adrenergic agonist. Mivazerol was also a potent competitor for [ 3H]RX 821002 binding to human platelet membranes (containing α 2A adrenoceptors) and rat kidney membranes (75 % of the α 2 adrenoceptors of the α 2B subtype), indicating that this compound is not α 2 adrenoceptor subtype selective. Equilibrium dissociation constants for α 1 adrenoceptors (displacement of [ 3H]prazosin) and 5-HT 1A receptors (displacement of [ 3H]rauwolscine) were respectively about 120 times ( K i = 4.4 μM) and 14 times ( K i = 530 nM) higher than that for the α 2 adrenoceptors. Equilibrium dissociation constants were approximately 1000 times higher for all other receptors tested in this study; namely β 1 and β 2 adrenoceptors, D 1- and D 2-dopamine receptors, M 1-, M 2- and M 3-muscarinic receptors, 5-HT 2 receptors and non-adrenergic idazoxan bindings sites.