ALPHA-1 ADRENOCEPTOR ANTAGONIST EFFECTS OF THE OPTICAL ISOMERS OF YM-12617 IN RABBIT LOWER URINARY-TRACT AND PROSTATE

Abstract

The alpha-1 adrenoceptor antagonist effects of the optical isomers of YM-12617 (5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide HCl), a potent and selective alpha-1 adrenoceptor antagonist, were evaluated in the rabbit lower urinary tract and prostate. R-(-)-YM-12617 (1 .times. 10-10 to 3 .times. 10-9 M) and S-(+)-YM-12617 (3 .times. 10-8 to 3 .times. 10-7 M) antagonized phenylephrine-induced contraction in a competitive manner in the urinary bladder base (trigone), proximal urethra and prostate. The mean pA2 value of R-(-)-YM-12617 at the alpha-1 adrenoceptor of trigone, urethra and prostate was 9.91, 9.62 and 9.92, respectively, and that for S-(+)-YM-12617 was 8.09, 7.92 and 7.77, respectively. Therefore, R-(-)-YM-12617 is a 50 to 141 times more potent antagonist than S-(+)-YM-12617 at the alpha-1 adrenoceptor in these tissues. The present results also indicate that the alpha-1 adrenoceptor in the lower urinary tract and prostate can distinguish clearly between the optical isomers of YM-12617. Similar results were obtained in the aorta of rabbits in which a dramatic stereochemical preference of R-(-)-YM-12617 for the alpha-1 adrenoceptor also exists.