Synthesis and Biological Evaluation of Antagonist Analogs of the Peptide Hormone Oxytocin

Abstract

Introduction Oxytocin (OT) is a mammalian nonapeptide hormone synthesized by the magnocellular neurons of the hypothalamus [1]. Among other functions, OT is responsible for the contraction of uterine smooth muscle at the onset of childbirth [2]. Antagonists of OT, such as atosiban 1 [3a] and peptide 2 [3b] (Fig. 1) are of interest as tocolytic agents that inhibit preterm labor and delay premature birth. There are an estimated 13 million premature births worldwide per annum [4a,b] that account for 66% of all neonatal mortality and contribute to serious complications and infant morbidity [4c]. Unfortunately peptides like 1 have relatively short metabolic half-lives are usually administered intravenously due to lack of metabolic stability [3b]. We have recently shown that analogs of OT, in which the disulfide bridge is replaced with an unsaturated ethylene linker with a cis conformation yields an analog with potent agonistic activity (EC50 = 38 nM) [5a]. Using a similar approach, we wanted to explore the synthesis and biological spectrum of a variety of 1,6-dicarba analogs of 2 and 3.