TISSUE SELECTIVITY OF KMD-3213, AN α 1-ADRENOCEPTOR ANTAGONIST, IN HUMAN PROSTATE AND VASCULATURE

Abstract

We evaluated the binding and functional affinity of KMD-3213 and other alpha 1-adrenoceptor (AR) antagonists such as prazosin or tamsulosin, to compare the tissue selectivity of these antagonists between human prostate and vasculature. In the binding experiments, saturation experiments using [3H]-KMD and [3H]-prazosin (PZ) were performed, and competition of [3H]-PZ binding by antagonists was also examined in human prostatic and aortic membranes. In the functional study, contractile responses to noradrenaline were evaluated in human prostate and mesenteric artery. [3H]-PZ bound to human prostatic and aortic membranes with subnanomolar affinity. [3H]-KMD also bound to human prostate, with higher affinity than [3H]-PZ; whereas it did not bind sufficiently to human aorta. Competition of [3H]-PZ binding revealed that KMD-3213 had more than 200-fold higher affinity for human prostate than for aorta. Binding profiles of antagonists revealed that human prostate predominantly expressed alpha 1A-AR, whereas human aorta expressed alpha 1B-AR mainly. In functional experiments, KMD-3213 potently inhibited the noradrenaline-induced contraction in human prostate as potently as tamsulosin, although prazosin showed relatively low affinity. Comparing these functional affinities with those in the mesenteric artery, only KMD-3213 exhibited substantial tissue selectivity, showing more than 100-fold higher affinity for human prostate than for mesenteric artery. Functional affinity of each antagonist suggested that noradrenaline-induced contractions were mainly mediated by alpha 1L-AR in the human prostate and by alpha 1B-AR in the mesenteric artery. These results suggest that KMD-3213 is a substantially prostate-selective alpha 1-AR antagonist in human tissues compared with other alpha 1-AR antagonists.