シロドシン(KMD-3213)のα_1-アドレナリン受容体サブタイプ選択性及び臓器特異性(<特集>シロドシン)

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The selectivity of silodosin (KMD-3213), an antagonist of α_1-adrenoceptor (AR), to the subtypes (α_<1A>-, α_<1B>- and α_<1D>-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other α_1-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 α_1-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of α_1-AR subtypes (α_<1A>-AR: rabbit prostate, urethra and bladder trigone; α_<1B>-AR: rat spleen; α_<1D>-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 α_<1A>-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 pA_2 or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA_2 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 α_1-AR antagonists. Our data suggest that silodosin has a high selectivity for the α_<1A>-AR subtype and for the lower urinary tract.
2006-03-01

シロドシン(KMD-3213)のα_1-アドレナリン受容体サブタイプ選択性及び臓器特異性(<特集>シロドシン)

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