ADH Antagonists

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Since the synthesis of ADH (shown in Fig. 3) by Du Vigneaud and colleagues [ 19], innumerable modifications of the peptide structure have been attempted, in order to develop specific antagonists to the different ADH receptor subtypes [31]. There are three receptor subtypes, all of which are membranes of the 7 membrane spanning G-protein-linked receptor family. V1A receptors are present in vascular and hepatic tissues, where they mediate vasoconstriction and glycogenolysis. V1B receptors, located in the anterior pituitary, mediate release of ACTH in response to ADH [60]. Both types of V! receptors act via the phos-phoinositide pathway. V2 receptors are located in collecting duct cells, where they stimulate insertion of water channel-containing vesicles into the normally water-tight apical membrane via stimulation of adenylate cyclase and its attendant protein kinases (protein kinase A) [60]. With the recent cloning of the V2 receptor, it has become clear that most patients with congenital nephrogenic diabetes insipidus lack a functional V2 receptor, emphasizing the potential therapeutic value of V2 receptor antagonists [7]. Initial attempts to design selective V2 antagonists focused on peptide derivatives [31], Although some selective derivatives were developed that were successful in rats, these demonstrated agonist properties in humans and dogs [31]. In addition, peptide analogs were suitable for parenteral administration only.

NH2n h2c

CH — C — Tyr — Phe — Gin — Asn —Cys — Pro — Arg — Gly —NH2

FIGURE 3. Structures of antidiuretic hormone (ADH) and the selective V2 antagonist, OPC-31260.

OPC-31260

FIGURE 3. Structures of antidiuretic hormone (ADH) and the selective V2 antagonist, OPC-31260.

Recently, selective nonpeptide ADH antagonists have been developed by extensive drug screening programs [57], Following the successful development of V! receptor antagonists, further derivatization yielded a compound, OPC-31260 (see Fig. 3), which bound selectively to V2 receptors, exhibiting 50% inhibition of [3H] ADH binding at 1.2 X 10 6 M for V! receptors and at 1.4 X 10"8 M for V2 receptors [57]. Unlike earlier peptide-based inhibitors, the compound exhibited no antidiuretic agonist activity when injected into rats with hereditary diabetes insipidus (Brattleboro rats) and strikingly raised urine volume and lowered urine osmolality in hydra ted conscious rats [57]. In humans, oral doses of 1 mg/kg increased urine volume to a similar degree as was observed with 0.33 mg/kg furosemide, but did so primarily by increasing free water clearance [41], Thus, the oral dose of OPC-31260 stimulated excretion of 500 ml of urine of osmolality below 70 mOsm/kg, while furosemide resulted in excretion of a similar amount of isosthenuric urine. The fact that OPC-31260 did not prevent dilution of urine when it was administered suggests that the stimulatory effect of ADH on thick ascending limb salt reabsorption is relatively minor in the human. Interestingly, OPC-31260 raised circulating ADH levels to double to triple their basal values, either by effecting a modest rise in serum osmolality or by another, possibly direct, effect on neurohypophyseal cells [41 ]. In addition, the compound elicited a modest increase in UNaV, suggesting that its antagonism of ADH binding blocked ADH-stimulated Na+ reabsorption in the collecting duct. At present, the effects of chronic administration of OPC-31260 are unknown, and it is apparently undergoing clinical trials [41].

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