Alpha-adrenoceptor activity of arylalkylimidazoles is improved by alpha-methylation and impaired by alpha-hydroxylation.

To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on the alpha-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 by alpha-hydroxylation and usually augmented by alpha-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 the alpha-position of the alkyl bridge did not decrease but even caused an increase in alpha-adrenoceptor activity in this test system. The detrimental effect of alpha-hydroxylation of the compounds at alpha 1- and alpha 2-adrenoceptors supports the notion that the interaction of the imidazoles at alpha-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.