Oxytocin metabolic activation

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

The deamino-dicarba-analogues of various biologically active cystine-containing peptides, such as oxytocin/1-3 calcitonin/31 32 and somatostatin/33-35 have shown high biological activity and enhanced metabolic and chemical stability owing to the absence of reducible disulfide linkages. 

Acknowledgment - This work was supported by Grant AM-10080 of the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service and by the U. S. Atomic Energy Commission. The authors wish to thank Dr. W. Y. Chan for independently evaluating the biological activities of crystalline deamino-1-seleno-oxytocin. 

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