Vasopressin-antagonists

Vasopressin antagonists include a range of compounds with varying selectivity, some of which have been in clinical use or in clinical trials since 2009 (Izumi Y et al. 2014; Imamura T et al. 2019).

The small molecule vasopressin receptor 2 (VR2) antagonists, known as vaptans , directly block the action of vasopressin at its receptors (V1A, V1B and V2). These receptors have a variety of functions, with the V1A and V2 receptors being peripherally expressed and involved in the modulation of blood pressure and renal function, respectively. The V1A and V1B receptors are expressed in the central nervous system. Thus, V1A has been associated with a variety of social behaviors in humans and animals.

Other compounds under development or in clinical trials include:

• Mozavaptan
• Satavaptan (V2-selective)
• Relcovaptan (V1A-selective).

Conivaptan is a US approved "dual" vasopressin antagonist that inhibits vasopression receptors V1b and V2.

Drugs of the "Vaptane group" directly block the action of vasopressin at its receptors (V1A, V1B and V2). These receptors have a variety of functions, with the V1A and V2 receptors being peripherally expressed and involved in the modulation of blood pressure and renal function, respectively. The V1A and V1B receptors are expressed in the central nervous system.

Vasopressin receptor antagonists (V2R antagonists) include the following indications:

• Hyponatremia: V2R antagonists (V2Ras) have value in the treatment of euvolemic (ie, SIADH, postoperative hyponatremia) and hypervolemic hyponatremia. V2RAs predictably cause aquaresis. For hyponatremia in neurologic and neurosurgical patients, conivaptan (conivaptan hydrochloride) (V1 / V2R antagonist) is the preferred agent. Selective V2R antagonists such as tolvaptan, lixivaptan, etc. are likely to be useful in patients for whom oral therapy is appropriate and in chronic forms of hyponatremia.
• Liver cirrhosis: V2R- antagonists may be useful in the treatment of patients with advanced liver cirrhosis and ascites. (Ajay K et al 2009). Blockade of V2R induced via the sysnthetic V2 receptor antagonists (e.g. satavaptan) induces effective aquaresis and inhibition of V2-mediated vasodilation. This aquaresis, in combination with diuresis, may represent a potential therapy for patients with resistant ascites. V2 receptor antagonism increases plasma vasopressin concentrations, which may lead to unopposed vasoconstrictor V1 receptor overstimulation. Given the potential overstimulation of V1R, V2RA may have additional secondary preventive benefits in patients with cirrhosis by reducing portal pressure and decreasing the risk of variceal bleeding (Ajay K et al 2009).
• Hyponatremia: V2R antagonists (V2Ras) have value in the treatment of euvolemic (i.e. SIADH, postoperative hyponatremia) and hypervolemic hyponatremia. V2RAs predictably cause aquaresis leading to elevated (Na +) in most patients with hyponatremia due to SIADH, CHF, and cirrhosis. For hyponatremia in neurologic or neurosurgical patients who cannot take oral medications, or in patients in whom more rapid correction of hyponatremia is desired, conivaptan (conivaptan hydrochloride) (V1 / V2R antagonist) is a potent agent (Buckley MS et al. (2013). Selective V2R antagonists like tolvaptan (Bockenhauer D 2017), lixivaptan etc are useful for patients suffering from chronic forms of hyponatremia.
• Liver cirrhosis: V2R- antagonists may be useful in the treatment of patients with advanced liver cirrhosis and ascites. (Ajay K et al 2009). Blockade of V2R induces effective aquaresis and inhibition of V2 mediated vasodilation. This aquaresis, in combination with diuresis, may be a potential therapy for patients with resistant ascites. V2 receptor antagonism increases plasma vasopressin concentrations, which may lead to unopposed vasoconstrictor V1 receptor overstimulation. Given the potential overstimulation of V1R, V2RA may have additional secondary preventive benefits in patients with cirrhosis by reducing portal pressure and decreasing the risk of variceal bleeding (Ajay K et al 2009).
• Nephrogenic diabetes insipidus: Congenital nephrogenic diabetes insipidus (NDI) can result from V2R or aquaporin-2 (AQP2) mutations. Exogenously administered V2R antagonists can bind to the misfolded intracellular V2 receptor (V2R) and enhance the transport of V2R to the cell membrane. Clinical studies in patients with X-linked NDI showed that the selective V1R antagonist relcovaptan significantly increased urine osmolality and decreased 24-hour urine flow.
• Autosomal dominant polycystic nephropathy (ADPKD1) (Q61.2) are characterized by mutations in the PKDD1 gene (16p13.3). Chronic hyponatremia is a common complication of this disease and is due to water retention. Clinical trials with a specific V2 receptor antagonist have shown a reduction in kidney size and cyst volume. Therapeutic trials with V2RA in patients with autosomal dominant polycystic kidney disease are currently ongoing (Bockenhauer D 2017).

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