?-Adrenoceptor activity of arylalkylimidazoles is improved by?-methylation and impaired by?-hydroxylation

To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on theα-adrenoceptor activity of arylalkylimidazole derivatives, the cardiovascular effects of the molecules were studied in anaesthetized and pithed rats. The compounds studied were 4(5)-substituted imidazole derivatives with a methano, ethano or etheno bridge between the imidazole and the 2-, 2,3- or 2,6-methyl substituted phenyl rings. The hypotensive and bradycardic activities of the molecules in the anaesthetized rat were always reduced byα-hydroxylation and usually augmented byα-methylation of the bridge between the imidazole and phenyl rings. Hydroxylation was associated with a consistent, marked decrease in vasopressor and sympatho-inhibitory activity in the cardiovascular system of the pithed rat, but a methyl moiety as a “bulky substituent” in theα-position of the alkyl bridge did not decrease but even caused an increase inα-adrenoceptor activity in this test system. The detrimental effect ofα-hydroxylation of the compounds atα1- andα2-adrenoceptors supports the notion that the interaction of the imidazoles atα-adrenoceptor is different from that of the classical, noradrenaline-like phenethylamines. The results also suggest that the alkyl bridge between the phenyl and imidazole rings of the imidazoles may contribute directly to the binding process.