Discrimination between peripheral and central α-adrenergic effects using meta-substituted imidazolidines

Abstract

meta-Substituted 2-chlorophenyl(imino)imidazolidines of the clonidine-type (2,3- and 2,5-substituted derivatives) were used in attempts to discriminate between α-adrenergic effects (central hypotensive and peripheral hypertensive activities) in rats. The central hypotensive activity of four pairs of substitution isomers was expressed as a pC 20, calculated from log dose-response curves after i.v. administration of the compounds to anaesthetized, normotensive rats. Peripheral hypertensive potency was evaluated in pithed normotensive rats following i.v. injections and quantified by means of pC 60. The partition coefficients of the drugs were determined in an octanol/aqueous buffer (pH 7.4, 37°C) system as a measure of lipophilic behaviour. The pressor activities in rats were comparable within each pair of substitution isomers whereas the depressor potencies differed greatly, although the representatives within each pair displayed similar lipophilicity. Regression analysis showed that the central hypotensive activity was governed by the steric bulk of the 5-substituent. On the other hand, this feature did not affect the peripheral hypertensive potency. The discrepancy between central and peripheral α-adrenergic activities found for 2,5-substituted imidazolidines is discussed in connection with the selectivity of these compounds for α 1- and α 2-adrenoceptors.