α2 adrenoceptor agonists as potential analgesic agents. 3. Imidazolylmethylthiophenes

Article abstract of DOI:10.1021/jm0003891

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the α₂ adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the α_2D adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED₅₀ doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.