Oxytocin, discovery

The discovery of peptide and protein hormones and peptide neurotransmitters began in the late nineteenth century with the discovery of the pituitary principles (now referred to as oxytocin, vasopressin, ACTH, a-mela-notropin,etc.). However, at the time it was not thought that these "principles" were peptides or proteins. That they were was first firmly established by duVigneaud and colleagues with the sequence of oxytocin (38) followed shortly thereafter by its total synthesis (39). A few years later Sanger et al. (40) determined the primary structure of insulin. These two seminal discoveries ended all the controversies, and established that peptides and proteins could be hormones, and later, peptide neurotransmitters were similarly discovered. Since then hundreds of peptide and protein hormones and neurotransmitters have been identified and their structures determined. 

Less than 50 years after the discovery of oxytocin in 1904 by Sir Henry Dale, who found that an extract from the human pituitary gland contracted the uterus of a pregnant cat, the biochemist du Vigneud synthesized the cyclic peptide hormone. His work resulted in the Nobel Prize in Chemistry in 1955. 

The potent (IC50 = 8.9 nM, rat uterus 26 nM, human uterus), orally available (bioavailability 21% in three species) oxytocin antagonist L-368,899 is currently undergoing clinical evaluation. The authors are continuing their efforts to increase the understanding of the relationship between the nonpeptide and peptidic oxytocin antagonists. The aim of this work is to develop a pharmacophore model that will assist in the discovery of new structural classes of antagonists. 

Some of the most successful ventures in peptide research took place in laboratories of the pharmaceutical industry. The Lederle Laboratories, with G.W. Anderson, J.R. Vaughan, Jr. and F.M. Callahan as principal investigators, made early contributions to the methodology of synthesis and to the synthesis of hormones such as oxytocin and calcitonin. The Squibb Institute for Medical Research was the first to report the synthesis of secretin, an effort led by Miklos Bodanszky. More recently the Institute scored a major success with the development of the first medically useful inhibitor of the angiotensin converting enzyme, an intellectually most appealing discovery of M.A. Ondetti (Plate 32). Another Squibb researcher, J.T. Sheehan (1913-1985), should be remembered for... 

Borthwick, A. D., Liddle, J. (2013). Retosiban and Epelsiban Potent and Selective Orally Available Oxytocin Antagonists. Protein-Protein Interactions in Drug Discovery Wiley-VCH Verlag GmbH, Weinheim. 

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