A molecular-orbital study of the structure-activity relationships of some imidazolidines related to clonidine

Abstract

Ab initio STO-3G MO calculations were performed for models of twenty imidazolidines related to clonidine. Regression analyses are reported which include electronic factors as well as parameters relating to molecular transport and size. Experimental data for the central hypotensive activity in normotensive rats following intravenous administration were recalculated with corrections for the amounts of basic and protonated forms and for the concentration of drug reaching the brain. The most important electronic parameter in the regressions reported is the LUMO energy which appears in the regressions considered with a positive coefficient. It is suggested that a charge-transfer interaction occurs involving the basic forms of the drug molecules, which leads to a reduction in hypotensive activity. An increase in hypotensive activity appears to follow an ionic interaction of the protonated drug species.