Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist

Abstract

[Mpa1, Glu4, Cys6, Lys8]oxytocin was prepared and found to be a very weak agonist in the oxytocic assay with about 1/1400 the potency of the native hormone. Bicyclization of this compound via a lactam bridge between the Glu4 δ-carboxyl group and the ϵ-amino group of Lys8 led to the bicyclic analogue 4,8-cyclo[Mpa1, Glu4, Cys6, Lys8]oxytocin. This bicyclic peptide acts as a very potent antagonist of oxytocin in the rat uterus assay with an in vitro pA2 value of 8.2. In the in vivo oxytocic assay the pA2 value was 6.45. The peptide displays mixed agonist/antagonist character in the in vivo galactogogic assay. The implications of these results to hormone agonist and antagonist activity are discussed with respect to earlier studies on constrained oxytocin antagonists and the results from the X-ray crystal structure of deaminooxytocin. © 1993, IEEE. All rights reserved. © 1990, American Chemical Society. All rights reserved.