Role of the carboxamide groups of the asparagine and glycinamide residues of oxytocin. Syntheses and biological properties of [5-beta-cyanoalanine] oxytocin and [9-alpha-aminoacetonitrile] oxytocin.

In an attempt to see whether the C=O and the NH2 of CONH2 of asparagine5 and glycinamide9 are both essential for biological activity, [5-beta-cyanoalanine] oxytocin and [9-alpha-aminoacetonitrile] oxytocin have been synthesized. Each of these analogs contains a nitrile group in place of the carboxamide group of Asn5 and GlyNH92 respectively; the nitrile group can simulate the carbonyl portion of the carboxamide, but lacks the hydrogen-bond donating capacity of its NH2 portion. Substitution of a nitrile group produced opposite biological effects in the 5 and the 9 positions; the 5-substituted analog showed very low activities (less than 3% of those of oxytocin) while the 9-substituted analog showed extremely high activities (with an in vivo uterine activity of 906 U/mg almost twice that of oxytocin). The results clearly suggest that the mechanisms of interaction of the carboxamide groups with the receptor sites are different for residues 5 and 9.