Oxytocin structure activity relationship

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Structure-Activity Relationships. Oxytocin and vasopressin are neurohypophyseal hormones synthesized in the hypothalamus and then transported along with their carrier proteins to the posterior lobe of the pituitary... 

Structure-Activity Relationships of Oxytocin. Hundreds of analogs of oxytocin have been synthesized since 1953. There have been several comprehensive reviews of this work (167-169). 

Wold, S., Eriksson, L., Hellberg, S Jonsson, J., Sjostrom, M., Skagerberg, B. and Wikstrdm, C. (1987) Principal property values for six non-coded amino acids and their application to a structure-activity relationship for oxytocin peptide analogues. Can.]. Chem., 65, 1814-1820. 

However, when trying to do this, one encounters a fundamental difficulty There would appear to be considerable differences in the sensitivity, i.e. the structure, of the oxytocin receptors. It is widely recognised that important species differences exist in the structtire of the receptors of a given organ (e.g. the uterus or the vessels responsible for blood pressure). But there seem to be similar important differences between the receptors of different organs (e.g. uterus, mammary gland and vessels) in the same species. This is probably one of the major reasons why it is so difficult to establish generally applicable structure/activity relationships. 

Wyatt, P. G. Allen, M. J. Chilcott, J. Jickin, G. Miller, N. D. Woollard, P. M. Structure-activity relationship investigations of a potent and selective benzodiazepine oxytocin antagonist. Bioorg. Med. Chem. Lett. 2001, 11, 1301-1305. 

When, after numerous unsuccessful attempts, oxytocin and vasopressin were finally isolated, one of the most fascinating chapters of the history of medicine was started. Most of the original work was done in Du Vigneaud s laboratory between 1932 and 1953. It involved oxytocin and vasopressin purification, investigation of their amino acid composition and sequence, synthesis of the polypeptides, and investigation of the relationship between secondary structure and activity of both these hormones. 

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