Oxytocin receptors, binding

Johnson AE The regulation of oxytocin receptor binding in the ventromedial hypothalamic nucleus by... 

Oxytocin and vasopressin are closely related peptides sharing seven out of nine amino acids. Vasopressin is able to bind to all vasopressin and oxytocin receptors with nanomolar affinity, whereas oxytocin has greater affinity for the oxytocin receptor than the vasopressin receptors. The affinity of the peptides for the receptors is shown in Table 7.1 (data from Mouillac et al. [20]). 

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... 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

Grazzini E, Guillon G, Mouillac B, Zingg HH. Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998 392 509-512. 

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. 

MOA Synthetic oxytocin is identical to natural oxytocin and binds to the oxytocin receptor on the uterine myometrium, causing contractions. Prostaglandins are also naturally synthesized by the body and cause uterine contractions. 

Similarly, a three-dimensional model of the vasopressin/oxytocin receptor has been defined and the binding mode of the neuropeptides has been analysed (Figure 3 and 5). Residues likely to contribute to the affinity, efficacy and selectivity have been proposed from the model. These qualitative predictions have subsequently been confirmed by site directed mutagenesis [20-22]. A number of general comments can be made ... 

Jojart, B., Martinek, T.A. and Marki, A. (2005) The 3D structure of the binding pocket of the human oxytocin receptor for benzoxazine antagonists, determined by molecular docking, scoring functions and 3D-QSAR methods. J. Comput. Aid. Mol. Des., 19, 341-356. 

The analogs discussed so far reveal certain features of the various oxytocin receptors. The molecule binds, however, not merely to the receptors in the target organs, but also to a carrier protein, originally known as the van Dyke protein [54] that was renamed neurophysin after its isolation in pure form. It is rather remarkable that for binding of oxytocin to this protein the free N-terminal amino group, which is not needed for activity, is quite essential [55]. 

T. L. Blundell, V.J. Hruby, A. Buku, A.J. Fischman, H.R. Wyssbrod, Crystal structure of deamino-oxytocin. Conformational flexibility and receptor binding. Science 232 633-636 (1986)... 

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