Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists

Quantitative relationships between in vitro affinity for Alpha 1- and Alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo Alpha 1/Alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the Alpha 1/Alpha 2-binding selectivity ratio most significantly correlated with the functional Alpha 1/Alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of Alpha 1-adrenoceptor-induced vasoconstriction and Alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of Alpha 1- and Alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro Alpha 1- and Alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional Alpha 1- and Alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, Alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with Alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for Alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound Alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) Alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for Alpha 1- and Alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which Alpha 1- and Alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)