1. (1-Beta-mercaptopropionic acid, 2-(3,5-dibromo-L-tyrosine))oxytocin, a potent inhibitor of oxytocin
E O Lundell, M F Ferger J Med Chem. 1975 Oct;18(10):1045-7. doi: 10.1021/jm00244a023.
[1-Beta-Mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was synthesized from a protected polypeptide intermediate that had been prepared by the condensation of S-ethylcarbamoyl-beta-mercaptopropionyl-3,5-dibromotyrosine with H-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2, using dicyclohexylcarbodiimide in dimethylformamide. The ethylcarbamoyl (Ec) protecting groups were removed by refluxing NH3, and the resulting disulfhydryl peptide was oxidatively cyclized to the corresponding disulfide by ICH2CH2I. Purification of the analog was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.05) and antiavian vasodepressor (pA2 = 7.44) activities but has neither agonist nor antagonist activity in the rat pressor assay.
2. (4-Phenylalanine)oxytocin, an inhibitor of the antidiuretic effect of 8-arginine-vasopressin
J J Nestor Jr, M F Ferger, W Y Chan J Med Chem. 1975 Oct;18(10):1022-4. doi: 10.1021/jm00244a014.
[4-Phenylalanine]oxytocin was prepared from Z-Cys(Bzl)-Tyr(Bzl)-Ile-Phe-Asn-Cys(Bzl)-Pro-Leu-Gly-NG2 (4) by deprotection with Na in NH3 followed by cyclization of the resulting disulfhydryl compound with ICH2CH2I. The protected peptide 4 was prepared from Boc-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwise solution method. Coupling was effected by a modification of the dicyclohexylcarbodiimide-1-hydroxybenzotriazole preactivation method wherein the precipitate of dicyclohexylurea is removed by filtration prior to mixing of the amino and carboxyl components. The analog was found to be an effective inhibitor of the antidiuretic (ADH) response to exogenous arginine-vasopressin. It produced marked diuresis in the anti-ADH assay at approximately the same dose level as does [Leu4]oxytocin but, in contrast to [Leu4]oxytocin, showed natriuretic activity only at relatively high dose levels. In addition, [Phe4]oxytocin exhibited 0.15% of the oxytocic potency of oxytocin, weak antiavian vasodepressor activity (pA2 = 6.93), and no measurable rat pressor activity.
3. Synthesis and some pharmacological properties of [1-beta-mercapto-beta,beta-diethylpropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin
E O Lundell, C W Smith, M F Ferger J Med Chem. 1975 Dec;18(12):1262-4. doi: 10.1021/jm00246a021.
The synthesis of the protected polypeptide precursor of [1-beta-mercapto-beta,beta-diethylpropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was performed in a stepwise manner by solution techniques. This analog of oxytocin has two modifications, each of which taken alone gives analogs which inhibit some of the pharmacological responses to oxytocin. The S-ethylcarbamoyl protecting groups of beta-Mpa(beta-Et2)(Ec)-Dbt-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2 were removed in refluxing liquid NH3, and the resulting disulfhydryl compound was oxidatively cyclized in H2O-MeOH with ICH2CH2I. Purification was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.08) and antiavian vasodepressor (pA2 = 7.38) activities but has neither agonist nor antagonist activity in the rat pressor assay. These potencies are close to those exhibited by [1-beta-mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin but different from those of [1-beta-mercapto-beta,beta-diethylpropionic acid]oxytocin.
