MEDETOMIDINE ANALOGS AS ALPHA(2)-ADRENERGIC LIGANDS .3. SYNTHESIS ANDBIOLOGICAL EVALUATION OF A NEW SERIES OF MEDETOMIDINE ANALOGS AND THEIR POTENTIAL BINDING INTERACTIONS WITH ALPHA(2)-ADRENOCEPTORS INVOLVING A METHYL POCKET

The synthesis and the biological evaluation of a new series of medetom idine analogs are reported. The substitution pattern at the phenyl rin g of the tetralin analogs had a distinct influence on the alpha(2)-adr enoceptor binding affinity. 4-Methylindan analog 6 was the most potent alpha(2)-adrenoceptor binding ligand among these 4-substituted imidaz oles, and its alpha(2)-adrenoceptor selectivity was greater than the 5 -methyl tetralin analog 4c. Ligand-pharmacophore and receptor modeling were combined to rationalize alpha(2)-adrenoceptor binding data of th e imidazole analogs in terms of ligand-receptor interactions. The stru cture-activity relationships that were apparent from this and previous studies were qualitatively rationalized by the binding site models of the alpha(2)-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl analog 2a was superimposable with the alpha-methyl gro up of (-)-alpha-methylnorepinephrine and fit into the proposed ''methy l pocket'' of the alpha(2)-adrenoceptor defined by the residues Leu110 , Leu169, Phe391, and Thr395.