Quantitative structure-activity relationships in centrally acting imidazolidines structurally related to clonidine.

ABSTRACT

The central hypotensive action of clonidine and 26 structurally related derivatives was quantified by means of an ED30 obtained from dose-response curves following intravenous administration to anesthetized, normotensive rats. Multiple regression analyses of the biological data yielded correlation equations comprising a relationship between hypotensive activity and molecular structure. In the equations the pharmacokinetics together with the actual engagement of the central alpha-adrenoceptor are accounted for. More detailed characteristics of this central alpha-adrenoceptor emerged from correlation studies in which new ED30 values, associated with brain concentrations, were employed. The use of this biological parameter at the alpha-adrenoceptor level allowed the presentation of a hypothetical working model for the mechanism of interaction between this receptive site and clonidine-like imidazolidines.