Synthesis of 2-p-methoxyphenylalanine oxytocin (O-Methyl-oxytocin) and some observations on its pharmacological Behavior

The synthesis of O-methyl-oxytocin, starting from p-methoxy-L-phenylalanine methyl ester, is described.. The pattern of the synthesis paralleled one used previously for the synthesis of oxytocin and involved the coupling of S-benzyl-N-carbobenzoxyl-L-cysteinyl-p-methoxy-L-phenylalanyl-L-isoleucyl-L-glutaminll-L-asparagine with S-benzyl-L-cysteinyl-L-prolyl-L-leucylglycinamide. Conversion of the resulting protected nonapeptide amide to O-methyl-oxytocin was effected by reduction with sodium in liquid ammonia followed by aeration. The methyl derivative of oxytocin was purified by countercurrent distribution and then compared with oxytocin as to some of its pharmacological effects. This hormone derivative containing P-methoxyphenylalanine in place of tyrosine possessed approximately 1% of the avian depressor and rat-uterine-contracting potency of oxytocin and showed no pressor activity in the rat. Furthermore, the O-methyl-oxytocin inhibited the pressor response of arginine-vasopressin when injected simultaneously with the pressor hormone into the rat.