(±)-Domesticine, a novel and selective α 1D-adrenoceptor antagonist in animal tissues and human α 1-adrenoceptors

Abstract

The pharmacological profile of (±)-domesticine, a novel α 1-adrenoceptor antagonist, was examined in animal tissues and Chinese hamster ovary (CHO) cells expressing cloned human α 1-adrenoceptor subtypes and compared with the properties of BMY-7378 ([8-(2-[4-(2-methoxy-phenyl)-1-piperazinyl]ethyl)-8-azaspirol [4.5]decane-7,9-dione dihydrochloride], the prototypical α 1D-adrenoceptor antagonist. Both (±)-domesticine and BMY-7378 were more potent in inhibiting the phenylephrine-induced contraction in rat thoracic aorta than tail artery or spleen. The selectivity of (±)-domesticine to inhibit phenylephrine-induced contraction in rat thoracic aorta was 32- and 17-fold higher than that in tail artery and spleen, respectively, while that of BMY-7378 it was 125- and 11-fold, respectively. The functional affinity profiles of these compounds for the α 1-adrenoceptor subtypes in animal tissues were consistent with the respective binding affinity profiles in cloned human α 1-adrenoceptor subtypes. (±)-Domesticine displayed a 34- and 9-fold higher selectivity for α 1d-adrenoceptor than for α 1a- and α 1b-adrenoceptor, respectively, while BMY-7378 showed a selectivity for α 1d-adrenoceptor of 102-fold higher than that of α 1a-adrenoceptor and 21-fold higher than that of α 1b-adrenoceptor. Interestingly, in [ 3H]8-OH-DPAT (8-hidroxy-2-(di- n-propyl-amino)tetraline hidrobromide) binding to 5-HT 1A receptors of rat cerebral cortex, (±)-domesticine showed a 183-fold higher selectivity for α 1D-adrenoceptor relative to 5-HT 1A receptor, whereas BMY-7378 displayed a similar affinity at this receptor with respect to the α 1D-adrenoceptor (0.89-fold). Both compounds, however, showed a weak affinity for 5-HT 2A/5-HT 2C receptors in rat frontal cortex. These results suggest that (±)-domesticine is more potent for α 1D-adrenoceptor than for α 1A- or α 1B-adrenoceptor subtypes and it is highly selective compared to 5-HT 1A and other receptors.