New Topics in Vasopressin Receptors and Approach to Novel Drugs: Research and Development of Conivaptan Hydrochloride (YM087), a Drug for the Treatment of Hyponatremia

Abstract

Hyponatremia is the most common electrolyte disorder in hospitalized patients and is associated with the risk of intractable seizures and death. The effectiveness of conventional therapies for hyponatremia is inconsistent, and the rapid correction of plasma sodium levels is thought to result in the occurrence of neurological complications. Arginine vasopressin (AVP) is the primary regulator of renal electrolyte-free water reabsorption via AVP-receptor type 2 (V2-R), and inappropriate or excessive AVP secretion independent of serum osmolality frequently causes excessive water retention, which is the etiological basis of hyponatremia. Therefore, the use of V2-R antagonists as anti-hyponatremic drugs in the clinical setting is anticipated to be reliable and safe. Conivaptan hydrochloride (YM087) is a novel dual AVP–R antagonist for AVP-R types 1a (V1a) and V2-R. In vitro studies have shown that it possesses high affinity for V1a-R and V2-R without any species differences. It also potently inhibited AVP-induced intracellular signaling through human V2 and V1a receptors with no agonistic activity. Conivaptan hydrochloride improved the plasma sodium concentration and plasma osmolality in hyponatremic rats, and its effectiveness was demonstrated in hyponatremic patients. This drug has been approved for use in the United States, which will bring relief to patients with hyponatremia.