Synthesis and structure-activity of 4(5)-(2,2-diphenylethyl)imidazoles as new α2-adrenoreceptor antagonists

Article abstract of DOI:10.1016/0223-5234(90)90180-B

4(5)-(2,2-diphenylethyl)imidazole 6a is described as being a potent (pK(i) = 8.16 for displacement of [³H] p-aminoclonidine) and selective (selectivity = -log (pK(i) α₂ - pK(i) α₁) = 81) α₂-adrenoreceptor antagonist (pA₂ = 8.73 versus clonidine in the electrically stimulated guinea pig ileum) with additional activity as a norepinephrine uptake inhibitor (IC₅₀ = 0.3 μM). An investigation of the structure-activity relationships of compounds closely related to 6a has been carried out. This included substitution of the phenyl and imidazole rings and modification of the link between these two ring systems. The various synthetic routes used are described. The affinity and the selectivity of the compounds for the α₂ site were determined by studying the displacement of [³H] p-aminoclonidine and [³H] WB-4101 from rat forebrain membranes. The efficacy of the compounds was defined by measuring the antagonism of the clonidine effect on the electrically stimulated guinea pig ileum.