title: Medetomidine analogs as alpha 2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with alpha 2-adrenoceptors involving a "methyl pocket".
abstract: The synthesis and the biological evaluation of a new series of medetomidine analogs are reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct influence on the alpha 2-adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent alpha 2-adrenoceptor binding ligand among these 4-substituted imidazoles, 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 the imidazole analogs in terms of ligand-receptor interactions. The structure-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 group of (-)-alpha-methylnorepinephrine and fit into the proposed "methyl pocket" of the alpha 2-adrenoceptor defined by the residues Leu110, Leu169, Phe391, and Thr395.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J E
authors.initials: JE
authors.lastname: De Los Angeles
authors.forename: M Y
authors.initials: MY
authors.lastname: He
authors.forename: J T
authors.initials: JT
authors.lastname: Dalton
authors.forename: G
authors.initials: G
authors.lastname: Shams
authors.forename: L
authors.initials: L
authors.lastname: Lei
authors.forename: P N
authors.initials: PN
authors.lastname: Patil
authors.forename: D R
authors.initials: DR
authors.lastname: Feller
authors.forename: D D
authors.initials: DD
authors.lastname: Miller
authors.forename: F L
authors.initials: FL
authors.lastname: Hsu
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D020926:Medetomidine; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D009281:Naphthalenes; D018341:Receptors, Adrenergic, alpha-2; D020926:Medetomidine