抄録
The selectivity of silodosin (KMD-3213), an antagonist of α1-adrenoceptor (AR), to the subtypes (α1A-, α1B- and α1D-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other α1-AR antagonists. In the receptor-binding study, a replacement experiment using [3H]-prazosin was conducted using the membrane fraction of mouse-derived LM (tk-) cells in which each of three human α1-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of α1-AR subtypes (α1A-AR: rabbit prostate, urethra and bladder trigone; α1B-AR: rat spleen; α1D-AR: rat thoracic aorta). Using the Magnus method, we studied the inhibitory effect of silodosin on noradrenaline-induced contraction, and compared it with those of tamsulosin hydrochloride, naftopidil and prazosin hydrochloride. Silodosin showed higher selectivity for the α1A-AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride (affinity was highest for tamsulosin hydrochloride, followed by silodosin, prazosin hydrochloride and naftopidil in that order). Silodosin strong antagonized noradrenaline-induced contractions in rabbit lower urinary tract tissues (including prostate, urethra and bladder trigone, with pA2 or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA2 values for antagonism of noradrenaline-induced contractions in rat isolated spleen and rat isolated thoracic aorta were 7.15 and 7.88, respectively. Selectivity for lower urinary tract was higher for silodosin than for the other α1-AR antagonists. Our data suggest that silodosin has a high selectivity for the α1A-AR subtype and for the lower urinary tract.
