Vasopressin receptor antagonists

Other potential oxytocia antagonists are being developed using leads from naturally occurring, nonpeptide stmctures, such as an extract from Streptomjces (48). A selective nonpeptide vasopressin receptor antagonist also has been found (49). 

Several nonpeptidic, orally active vasopressin receptor antagonists have been developed. The dual V1A/V2R antagonist conivaptan is used in the treatment of hyponatraemia and could also become useful for diseases such as congestive heart failure, in which increased peripheral resistance and dilutional hyponatremia both are present [4]. Side effects of conivaptan include headache, injection site reactions, vomiting, diarrhoea, constipation and thirst. 

Thibonnier M, Coles P, Thibonnier A, and Shoham M. The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Ann Rev Pharmacol Toxicol 2001 41 175-202. 

Vasopressin receptor antagonists, such as relcovaptan (an antagonist at Vla receptors), lixivaptan and tolvaptan (V2), and conivaptan (mixed V a/V2), are also under development (1). 

Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G. Nonpeptide vasopressin receptor antagonists development of selective and orally active Via, V2 and Vlb receptor ligands. Prog Brain Res 2002 139 197-210. 

Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, Thomas I, Ghah JK, Selaru P, Chanoine F, Pressler ML, Konstam MA. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001 104(20) 2417-23. 

Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N. Efficacy and safety of oral conivaptan a V1A/v2 vasopressin receptor antagonist, assessed in a... 

Schrier RW, Cadnapaphomchai MA, Umenishi F. 2001. Water-losing and water-retaining states role of water channels and vasopressin receptor antagonists. Heart Disease 3 210-214. 

Russell SD, DeWald T. Vasopressin receptor antagonists. Therapeutic potential in the management of acute and chronic heart failure. Am J Cardiovasc Drugs. 2003 3 13-20. 

Before the introduction of specific vasopressin receptor antagonists, pharmacological treatments for hyponatremia centered on the use of loop diuretics and nonspecific inhibitors of vasopressin signaling, such as lithium carbonate and demeclocycline.11 The utility of such therapies has been limited by a range of sideeffects. Loop diuretic use can result in electrolyte imbalances and suffers from poor response predictability.11 Lithium carbonate suffers from a low therapeutic index and a risk of renal damage as well as limited effectiveness in many patients. Lithium carbonate has therefore been nearly completely supplanted by demeclocycline, a tetracycline antibiotic, in the treatment of chronic hyponatremia.12 Demeclocycline use is itself limited by its nephrotoxicity (particularly in cirrhotic patients), ability to cause reversible uremia, and ability to induce photosensitivity.1,11... 

As Of 2009, conivaptan HCl (1) is one of three vasopressin receptor antagonists approved for use in the treatment of hyponatremia worldwide. The U.S. approval of 1 was preceded by the 2006 approval of mozavaptan hydrochloride (2) in Japan. In 2009, tolvaptan (3) joined 1 as an FDA-approved agent for the treatment of hyponatremia. In this chapter, the pharmacological profile and synthesis of conivaptan hydrochloride (1) is examined in detail. 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

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. 

Table 2. Vasopressin Receptor Antagonist Activities In Vitro and In Vivo.23,24,26...

Conivaptan HCl (1) is a potent dual Vla and V2 vasopressin receptor antagonist that increases water excretion without significant electrolyte depletion. 

This is indeed the case. In addition to gamma-aminobutyric acid (GABA), opiate and cholecystokinin receptor activities, the benzodiazepine scaffold is also found in muscle relaxants, antidepressants, neuroleptics, hypnotics, NK-1 receptor and vasopressin receptor antagonists, integrin antagonists, farnesyl transferase and phosphodiesterase inhibitors, potassium channel modulators, and others. 

Mittal S, Wu Z, Neelavalli J, Haacke EM (2009) Susceptibility-weighted imaging technical aspects and clinical applications, part 2. AJNR Am J Neuroradiol 30 232-252 Molnar AH, Varga C, Berko A, Rojik 1, Parducz A, Laszlo F, Laszlo FA (2008a) Prevention of hypoxic brain oedema by the administration of vasopressin receptor antagonist OPC-31260. Prog Brain Res 170 519-525... 

Shuaib A, Xu WC, Yang T, Noor R (2002) Effects of nonpeptide V( 1) vasopressin receptor antagonist SR-49059 on infarction volume and recovery of ftmction in a focal embolic stroke model. Stroke 33 3033-3037... 

Wong, F., Biel, A.T., Blendls, L.M., Thuluvath, R A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia a multicenter, randomized, placebo-con-trolled trial. Hepatology 2003 37 182-191... 

OPC 21268 is a quinolinone derivative, a selective (V1 subtype) vasopressin receptor antagonist, with antihypertensive properties,... 

AVP), except in the pig which has a Lys residue (iysine vasopressin). Oxytocin differs from vasopressin in having leucine at position 8 and isoleucine at position 3. Vasopressin and oxytocin analogues with some degree of receptor subtype selectivity that have been synthesized have ANTIDIURETIC or vasoconstrictor or OXYTOCIC (uterine-contracting) activity. See VASOPRESSIN RECEPTOR AGONISTS VASOPRESSIN RECEPTOR ANTAGONISTS. 

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