SYNTHESIS, PHARMACOLOGICAL, CONFORMATIONAL, AND DYNAMIC STUDIES OF THE POTENT HORMONE ANTAGONISTS [1‐PENICILLAMINE, 4‐THREONINE]‐OXYTOCIN AND [1‐PENICILLAMINE, 2‐PHENYLALANINE, 4‐THREONINE] ‐OXYTOCIN

Abstract

The solid phase synthesis of [1-penicillamine, 4-threonine]-oxytocin and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin is reported. The 2 compounds have no in vitro milk ejecting activity and no in vivo or in vitro oxytocic activity, but both are potent antagonists in these 3 assay systems. In the in vitro oxytocic assay, [1-penicillamine, 4-threonine]- and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin have pA2 values of 7.55 .+-. 0.04 and 7.67 .+-. 0.02, respectively, and both inhibit the uterine contractile response to oxytocin in nonpregnant and pregnant rats. [1-Penicillamine, 2-phenylalanine, 4-threonine]-oxytocin has a weak antipressor activity and at high doses, consistently caused a weak and transient fall in blood pressure in the rat. Carbon-13 NMR chemical shift parameters and spin-lattice relaxation times (T1) indicate that these 2 new oxytocin antagonists have very similar conformation and dynamic properties to oxytocin inhibitors which were previously examined. These results are discussed in terms of conformational and dynamic models of oxytocin antagonism at the uterus. Conformational restrictions at the 2- and 4-positions of penicillamine-1 analogs of oxytocin may be important to antagonist activity and potency.