Vasopressins 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... 

B. Aniline Derivatives - A structure-activity study of a new series of alkoxyaniline derivatives has been reported along with a detailed workup of one of them . This compound (XII) appears to have good analgesic and anti-inflammatory activity, associated with some CNS depressant effects. An antidiuretic effect was described for acetaminophen 9 a d it was suggested that this drug might be a useful substitute for vasopressin in certain patients with diabetes insipidus. Evidence was also presented to show that acetophenetidin has antipyretic activity which is not dependent on metabolism to N-acetyl-p-aminophenol. 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

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. 

Figure 2 Proneuropeptides structural features for proteolytic processing. Neuropeptides are synthesized as proneuropeptide precursors, also known as prohormones, that require proteolytic processing to liberate the active neuropeptide. Proteolytic processing occurs at dibasic and monobasic sites, as well as at multibasic sites. The precursor proteins may contain one copy of the active neuropeptide, such as the proneuropeptides for NPY, galanin, CRF, and vasopressin. Some proneuropeptides such as proenkephalin contain multiple copies of the active neuropeptide proenkephalin contains four copies of (Met)enkephalin (ME), one copy of (Leu)enkephalin (LE), and the related opioid peptides ME-Arg-Phe (H) and ME-Arg-Cly-Leu (O).

Classical enzyme inhibitors such as bacitracin, bes-tatin, and amastatin have been found to be effective for improving the nasal absorption of various peptide drugs such as LHRH and calcitonin. These inhibitors having peptide like structures appear to exert their inhibitory effects by a competitive mechanism. In addition, camostat mesilate and nafamostat mesilate, which are clinically used as primary ingredients for pancreatic diseases, have been found to improve the nasal absorption of vasopressin, desmopressin, and calcitonin by inhibiting aminopeptidase and trypsin activity. 

---