Pharmacological, conformational and dynamic properties of cycloleucine-2 analogues of oxytocin and [1-penicillamine]oxytocin

The solid phase syntheses of [2‐cycloleucine]oxytocin and [1‐penicillamine, 2‐cycloleucine]oxytocin are reported. [1‐Penicillamine, 2‐cycloleucine]oxytocin is an oxytocin antagonist exhibiting no in vitro oxytocic activity. In the in vitro oxytocic assay, [1‐penicillamine, 2‐cycloleucine]oxytocin has a pA2 value of 6.70 ± 0.08. [2‐Cycloleucine]‐oxytocin is a full oxytocin agonist exhibiting 4.9 ± 0.5 U/mg of oxytocic activity. Neither compound possesses any measurable agonist or antagonist activity in the rat pressor assay. Carbon‐13 nuclear magnetic resonance chemical shift parameters and spin‐lattice relaxation times (T1) of the antagonist, [1‐penicillamine, 2‐cycloleucine]oxytocin, indicate that the antagonist exhibits similar conformational and dynamic properties as other oxytocin inhibitors previously studied. The carbon‐13 nuclear magnetic resonance shift parameters and spin‐lattice relaxation times (T1) of the oxytocin agonist, [2‐cycloleucine] oxytocin, indicate that the agonist exhibits similar conformational and dynamic properties as oxytocin. These results are discussed in terms of the different receptor requirements for agonist and antagonist activities. It appears that there are different structural and conformational requirements at the 2‐position for oxytocic agonist and antagonist activities.