[1-.beta.-Mercapto-.beta.,.beta.-pentamethylenepropionic acid]oxytocin, a potent inhibitor of oxytocin

Abstract

[1-Beta-mercapto-beta,beta-pentamethylenepropionic acid]oxytocin was prepared from beta-Mpa(beta-(CH2)5)(Bzl)-Tyr(Bzl)-Ile-Gln-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by removal of the Bzl-protecting groups with Na-NH3 followed by cyclization of the resulting disulfhydryl compound with K3Fe(CN)6.The analog was purified by desalting on Sephadex G-15 in 50% HOAc and gel filtration on Sephadex G-25 and LH-20. The protected intermediate above was synthesized from Z-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwose p-nitrophenyl ester method using Nalpha-Boc protection at the penta-, hexa-, and octapeptide stages. The analog was found to be a potent inhibitor of the oxytocic and avian vasodepressor effects of oxytocin (pA2 values of 7.43 and 8.30, respectively) but was only a weak inhibitor of the rat pressor effect of 8-lysine-vasopressin. The rat antipressor potency of [1-deaminopenicillamine]oxytocin was also determined in this study: pA2 = 6.27. Of the alkyl-substituted 1-position analogs of oxytocin studied so far, [1-beta-mercapto-beta,beta-pentamethylenepropionic acid]oxytocin is the most potent antioxytocic agent.