Oxytocin structure-activity

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. 

Name and abbreviated chemical formula Structure of amino acid in position 8 Oxytocin-like activities in International Units per micromole References... 

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. 

Hormones related to oxytocin and vasopressin occur in most vertebrates, the compound vasotocin shown in Fig. 30-4 being the most common. Substitution of phenylalanine for isoleucine at position 3 gives arginine vasopressin, the vasopressin found in our bodies. Structure of oxytocin and related hormones82 are also shown in Fig. 30-4. Like somatostatin, vasopressin and oxytocin may also form antiparallel pleated sheet structures with P turns. The structural requirements for hormone activity have been studied intensively. Both the macrocyclic hexapeptide ring and the tripeptide side chains are necessary for maximal activity.83... 

In CHO cells transfected with human V], and V2 vasopressin receptors, 1 inhibits [3H]-AVP binding with K/s of 4.3 and 1.9 nM, respectively.15 Compound 1 demonstrates similar activity on rat Vla and V2 receptors, with Kj s of 0.48 nM and 3.0 nM (Table 1). As a result of significant structural homology between the vasopressin and the oxytocin receptors, 1 and AVP also demonstrate significant oxytocin receptor affinities (rat receptor Kt s of 44.4 nM and 3.4 nM, respectively).16 As seen in Table 1, the balanced binding affinities of 1 toward rat Via and V2 receptors closely parallel those of AVP in contrast, vasopressin receptor antagonists mozavaptan hydrochloride (2) and tolvaptan (3) demonstrate moderate to significant V2 receptor selectivity. 

After duVigneaud s proof of the biologically active structure of oxytocin by total synthesis... 

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