Mivazerol, a novel compound with high specificity for alpha 2 adrenergic receptors: binding studies on different human and rat membrane preparations.
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 alpha 2 adrenoceptors. Mivazerol displaced the binding of the alpha 2 adrenoceptor antagonist [3H]RX 821002 to the alpha 2A adrenoceptors in human frontal cortex membranes with an apparent Ki value of 37 nM. The competition curve was shallow (nH = 0.55), suggesting that this compound acts as an alpha 2 adrenergic agonist. Mivazerol was also a potent competitor for [3H]RX 821002 binding to human platelet membranes (containing alpha 2A adrenoceptors) and rat kidney membranes (75% of the alpha 2 adrenoceptors of the alpha 2B subtype), indicating that this compound is not alpha 2 adrenoceptor subtype selective. Equilibrium dissociation constants for alpha 1 adrenoceptors (displacement of [3H]prazosin) and 5-HT1A receptors (displacement of [3H]rauwolscine) were respectively about 120 times (Ki = 4.4 microM) and 14 times (Ki = 530 nM) higher than that for the alpha 2 adrenoceptors. Equilibrium dissociation constants were approximately 1000 times higher for all other receptors tested in this study; namely beta 1 and beta 2 adrenoceptors, D1- and D2-dopamine receptors, M1-, M2- and M3-muscarinic receptors, 5-HT2 receptors and non-adrenergic idazoxan binding sites.
UCB S.A. Pharma Sector, Chemin du Foriest, Braine-l'Alleud, Belgium.
M
M
Noyer
F
F
de Laveleye
G
G
Vauquelin
J
J
Gobert
E
E
Wülfert
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D004146:Dioxanes / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives; D007093:Imidazoles / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism
D004146:Dioxanes; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; C058525:2-methoxyidazoxan; C087969:mivazerol; D019329:Idazoxan