Medetomidine analogs as selective agonists for the human α 2-adrenoceptors

Abstract

α 2-Adrenoceptor (AR) agonists have therapeutic applications in a variety of diseases. Medetomidine, an α 2-AR agonist, belongs to 4-substituted imidazole class of compounds and is highly selective for the α 2-AR. The benzylic methyl group of medetomidine and naphthalene imidazole was proposed to interact with rat brain α 2-ARs via a methyl binding pocket in a manner analogous to its presence in α-methyl norepinephrine. A series of derivatives containing hydrophilic and hydrophobic substituents, as well as chiral and conformationally rigid analogs were used. In current binding and functional studies using human α 2-AR subtypes expressed in Chinese hamster ovary cells, optimal interactions were observed with the presence of the methyl group on the benzylic carbon atom of naphthyl imidazole. Data obtained with various analogs have demonstrated that size, electronegativity, lipophilicity, chirality and conformational flexibility of the substituents at the carbon bridge of naphthyl imidazole are important factors for interaction of the imidazole class of ligands with these α 2-AR subtypes. Taken collectively, the results obtained support the existence of the methyl binding pocket for optimal ligand receptor binding interactions in human α 2-AR subtypes. Further, the results also suggest that, additional modifications of medetomidine and naphthyl methyl imidazole at the benzylic carbon atom, and/or on the aromatic and imidazole ring systems could provide insights into the chemical requirements for optimizing α 2-AR subtype selectivity. This could eventually lead to the discovery of promising compounds for the evaluation of the physiological importance of the three α 2-AR subtypes.