196870-07-2Relevant articles and documents
Medetomidine analogs as α2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine
Zhang, Xiaoyan,Yao, Xiao-Tao,Dalton, James T.,Shams, Gamal,Lei, Longping,Patil, Popat N.,Feller, Dennis R.,Hsu, Fu-Lian,George, Cliff,Miller, Duane D.
, p. 3001 - 3013 (2007/10/03)
A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their α-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for α2-adrenoceptors and behaved as a partial α1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was α1-selective and behaved as a potent α1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at α1- vs α2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the α-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the α2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with α2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.
