Further studies on (±)-YM-12617, a potent and selective α1-adrenoceptor antagonist and its individual optical enantiomers

YM-12617, 5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide HCl is structurally novel, an extremely potent and highly selective α1-adrenoceptor antagonist. An asymmetric center exists at the α-carbon atom in the phenethylamine portion of YM-12617, therefore two optical enantiomers exist. α-Adrenoceptor blocking properties and hypotensive activities of YM-12617 and its enantiomers have been compared in vitro and in vivo. 1. In the isolated rabbit aorta, R(−)- and S(+)-YM-12617 competitively antagonized phenylephrine-induced contraction with pA2 values of 9.95 and 7.69, respectively. Although R(−)- and S(+)-YM-12617 were also competitive antagonists toward UK-14,304 at prejunctional α2-adrenoceptors in the isolated guinea-pig ileum, the affinities of R(−)-YM-12617 (pA2 = 6.18) and S(+)-YM-12617 (pA2 = 5.64) for these receptors were 5,900 and 110 times lower than those displayed for postjunctional α1-adrenoceptors in the isolated rabbit aorta. 2. R(−)- and S(+)-YM-12617 displaced both 3H-prazosin and 3H-idazoxan binding to rat brain membranes; however, the affinities of the R(−)- and S(+)-enantiomers for α1-adrenoceptors (pKi = 9.95 and 7.83, respectively) were 21,000 and 72 times higher than those for α2-adrenoceptors (pKi = 5.62 and 5.97), respectively. 3. Based on pA2 values obtained in the isolated tissues and pKi values in the binding assays, R(−)-YM-12617 was 132–182 times more potent than S(+)-YM-12617 as an antagonist at α1-adrenoceptors. In contrast, the R(−)- and S(+)-enantiomers were similar in potency at blocking α2-adrenoceptors. 4. In normotensive pithed rats, R(−)- and S(+)-YM-12617 preferentially antagonized the α1-adrenoceptor mediated pressor effect of phenylephrine with DR10 values of 1.38 and 705 μg/kg i. v., respectively, although a high dose (3,000 μg/kg i.v.) also inhibited the effect of UK-14,304 at postjunctional α2-adrenoceptors. R(−)-YM-12617 exhibited an over 2,000-fold selectivity for postjunctional α1-adrenoceptors, and R(−)-YM-12617 was over 500 times more potent than S(+)-YM-12617 in antagonizing postjunctional α1-adrenoceptors based on DR10 values. 5. In anesthetized rats, R(−)- and S(+)-YM-12617 dose-dependently produced hypotension with ED20 values, doses required decreased mean blood pressure by 20%, of 0.64 and 61 μg/kg i. v., respectively. R(−)-YM-12617 exerted a 95 times more potent hypotensive activity than S(+)-YM-12617, and its isomeric activity ratio was consistent with that for α1-adrenoceptors but not α2-adrenoceptors. 6. The present results suggest that the high stereoselectivity of the optical enantiomers of YM-12617 is in the α1-adrenoceptor, but not in the α2-adrenoceptor, and their antagonist potency for α1-adrenoceptors is likely to contribute to the hypotensive effect.