Further validation of in vivo and in vitro pharmacological procedures for assessing the alpha 2/alpha 1-selectivity of test compounds: (1). Alpha-adrenoceptor antagonists.

Twenty one chemically dissimilar alpha-adrenoceptor antagonists were assessed in 7 different tests. The potencies of the compounds to protect rats from norepinephrine lethality were closely correlated with their potencies for inhibition of [3H]WB4101, but not of [3H]clonidine, [3H]idazoxan, [3H]rauwolscine or [3H]yohimbine binding to rat brain homogenates. The reverse was found for the potencies of the compounds to prevent the antidiarrheal effect of clonidine. The in vivo anti-norepinephrine/anti-clonidine potency ratios were highly correlated with the ratios between the in vitro potency to inhibit [3H]WB4101 binding on one hand and [3H]clonidine, [3H]idazoxan, [3H]rauwolscine or [3H]yohimbine binding on the other. The reliability of the above models for measuring alpha 1- and alpha 2-adrenoceptor antagonistic activity and selectivity is discussed.