Abstract

The present study was undertaken to test the relationship between binding affinity for alpha₁-adrenoceptors and functional antagonism of drug-induced effects mediated by this type of alpha₁-receptor sites for alpha-sympatholytic drugs. The radioligand [³H]prazosin was used to identify alpha₁-adrenoceptors in rat brain membranes. The specific binding of [³H]prazosin was rapid, reversible, saturable, and of high affinity (K_D = 0.21 nM) and involved a single class of binding sites (B_max = 95 fmoles/mg of protein). A variety of alpha-adrenoceptor blocking drugs inhibited the specific binding of [³H]prazosin (0.2 nM) according to sigmoid displacement curves from which the corresponding log IC₅₀ values were calculated. The binding sites of [³H]prazosin in rat cerebral membranes possessed the characteristics of alpha₁-adrenoceptors. Antagonists such as rauwolscine, tolazoline, yohimbine, and piperoxan, known as selective blocking drugs of alpha₂-adrenoceptors, were found to be weak competitors. However, 2-[(2',6'-dimethoxyphenoxyethyl)-aminomethyl]-1,4-benzodioxane (WB-4101) and unlabeled prazosin as well as two of its derivatives, 2-[4-(ethoxyethyloxy)-piperidine-1-yl]-4-amino-6,7-dimethoxyquinazoline (UK-18,596) and 2-[4-(2-(1,4-benzodioxoyl))-piperazine-1-yl]-4-amino-6,7-dimethoxyquinazoline (UK-33,274), which have been classified as antagonists preferably occupying alpha₁-adrenoceptors, strongly interfered with this binding. The same alpha-adrenolytic drugs were studied with respect to their antagonism of (-)-phenylephrine-induced increases in diastolic pressure mediated via vascular, postsynaptic alpha₁-adrenoceptors in pithed, normotensive rats. This antagonism was quantified with the aid of pA₂ values. For the alpha-adrenoceptor antagonists studied (n = 21), the pA₂ in vivo correlated well with the log 1/IC₅₀ (r² = 0.86). Similarly, a close relationship was calculated between the binding data and reported pA₂ values with respect to the antagonism of alpha₁-adrenoceptor-mediated constrictor effects of the rabbit pulmonary artery in vitro (r² = 0.90). The results demonstrate that the binding affinity in vitro of antagonists for alpha₁-adrenoceptors corresponds with their functional antagonism of alpha₁-adrenoceptors in vivo and in vitro. Moreover, these findings point to a similarity among peripheral and central alpha₁-adrenoceptors.