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.
D000818:Animals; D001216:Asparagine; D001681:Biological Assay; D004231:Diuresis / Q000187:drug effects; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives*; D007202:Indicators and Reagents; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D051381:Rats; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
D007202:Indicators and Reagents; C018556:glycine amide; D010121:Oxytocin; D001216:Asparagine; C040172:oxytocin, 9 alpha-aminoacetonitrile-; C040173:oxytocin, beta-cyano-Ala(5)-; D005998:Glycine