Abstract

We have investigated the affinity and selectivity of tamsulosin and its metabolites, M1, M2, M3, M4 and AM1, at the tissue and the clonedalpha-1 adrenoceptor subtypes in the radioligand binding and the functional studies. In the radioligand binding studies, the compounds competed for [³H]prazosin binding to the rat liver and kidney alpha-1 adrenoceptors, with the rank order of potency tamsulosin ≈ M4 > M1 > M2 ≈ M3 ≫AM1 with the latter having a negligible affinity. All compounds differentiated cloned alpha-1 adrenoceptor subtypes with the rank order of potency of alpha-1A ≥alpha-1D > alpha-1B, except for M4 which had the highest affinity for the alpha-1D adrenoceptor. The compounds also concentration-dependently antagonized phenylephrine-induced contractions in the rabbit aorta and prostate. The resulting apparent pA₂ values were very similar to those at the cloned rat alpha-1A adrenoceptor. We conclude that most tamsulosin metabolites are high potency antagonists at the alpha-1 adrenoceptors and retain thealpha-1A over the alpha-1B adrenoceptor selectivity of tamsulosin.