1 RECEPTOR ANTAGONISTS Vasopressin V2 receptor antagonists J G Verbalis 232 Building D, Division of Endocrinology and Metabolism, Georgetown University School of Medicine, 4000 Reservoir Road NW, Washington DC 20007, USA (Requests for offprints should be addressed toJGVerbalis; Email: [email protected]) Abstract Hyponatremia, whether due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or disorders of water retention such as congestive heart failure and cirrhosis, is a very common problem encountered in the care of medical patients. To date, available treatment modalities for disorders of excess arginine vasopressin (AVP) secretion or action have been limited and suboptimal. The recent discovery and development of nonpeptide AVP V2 receptor antagonists represents a promising new treatment option to directly antagonize the effects of elevated plasma AVP concentrations at the level of the renal collecting ducts. By decreasing the water permeability of renal collecting tubules, excretion of retained water is promoted, thereby normalizing or improving hypo-osmolar hyponatremia. In this review, SIADH and other water retaining disorders are briefly discussed, after which the published preclinical and clinical studies of several nonpeptide AVP V2 receptor antagonists are summarized. The likely therapeutic indications and potential complications of these compounds are also described. Journal of Molecular Endocrinology (2002) 29, 1–9 Introduction heart failure (CHF) and cirrhosis with ascites. In these disorders, a relatively decreased intravascular Arginine vasopressin (AVP), the ‘antidiuretic volume and/or pressure leads to water retention as a hormone,’ is the major physiological regulator of result of both decreased distal delivery of glomerular renal free water excretion. Increased AVP secretion filtrate and secondarily elevated plasma AVP levels. causes an antidiuresis, with subsequent retention of For example, hyponatremic patients with advanced water by the kidney. Disorders of AVP secretion congestive heart failure often have inappropriately cause imbalances of body water. The most elevated plasma AVP levels, which fail to sup- prominent of these is the syndrome of inappropri- press completely even after acute water loading ate antidiuretic hormone secretion (SIADH). (Goldsmith et al. 1986). This occurs because low Patients with SIADH fail to suppress AVP secretion cardiac output causes an underfilling of the arterial even when the plasma osmolality falls below the vascular compartment, which unloads barorecep- normal osmotic threshold for stimulating AVP tors thereby activating the renin–angiotensin– secretion (Zerbe et al. 1980). Total body water aldosterone system, the sympathetic nervous system increases as a result of the impaired renal water and AVP secretion in an effort to increase vascular excretion, causing dilutional hypo-osmolality and resistance and enhance renal Na+ and water reten- hyponatremia (Verbalis 2001). The clinical criteria tion. Similar mechanisms occur in patients with required for a diagnosis of SIADH remain basically advanced cirrhosis and ascites with edema (Bichet the same as when the syndrome was first described et al. 1982); despite a generalized hypervolemic by Bartter and Schwartz in 1967. edematous state, there is avid renal Na+ and water Hypo-osmolar hyponatremia also occurs rela- retention in an attempt to maintain the effective tively frequently in advanced stages of congestive arterial blood volume (Schrier 1988). Journal of Molecular Endocrinology (2002) 29, 1–9 Online version via http://www.endocrinology.org 0952–5041/02/029–001 © 2002 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 08:49:37PM via free access 2 J G VERBALIS · Vasopressin V2 receptor antagonists Treatment strategies: disorders of at the V2 receptors in the collecting ducts of the hormone excess kidney. These agents, therefore, have the potential to increase free water excretion during states of Because SIADH is a disorder of relative AVP AVP excess, regardless of the cause of the AVP excess, it is rational to attempt to apply therapeutic hypersecretion. strategies similar to those used for other endocrine disorders of hormone excess. These include: (1) decreasing the secretion of the hormone, (2) AVP receptor subtypes decreasing the effects of the hormone at its target tissues, and (3) compensating for the effects All AVP receptor subtypes belong to the seven produced by the excess hormone secretion. transmembrane domain, G-protein-coupled recep- Although several drugs have been described that tor superfamily. Three known receptor subtypes decrease AVP secretion in some cases (e.g. ethanol, mediate all of the known actions of AVP; they are diphenylhydantoin, opiates), responses are erratic classified according to the second messenger system and often unpredictable. The second approach to to which they are coupled (Thibonnier et al. 1998). treating hormone hypersecretion, namely antago- The V1a and V1b (also known as V3) receptors are nizing the end-organ effects of the hormone, has linked to the phosphoinositol signaling pathway met with limited success. Until recently, pharmaco- with intracellular calcium acting as the second logical intervention for SIADH has been restricted messenger. In contrast, the V2 receptors are linked to drugs with predominantly post-receptor effects. to the adenylate cyclase signaling pathway with The tetracycline derivative, demeclocycline, causes intracellular cAMP acting as the second messenger. a nephrogenic form of diabetes insipidus, decreas- The V1a receptor subtype is ubiquitous and is ing urine concentration even in the presence of present on vascular smooth muscle cells, hepato- high AVP levels (Dousa & Wilson 1974). However, cytes and platelets where it mediates vascular demeclocycline can cause nephrotoxicity, especially constriction, glycogenolysis and platelet aggrega- in patients with cirrhosis, although in most cases tion respectively. V1b,orV3, receptors are found this has been reversible. Other agents, such as predominantly in the anterior pituitary where they lithium carbonate, have similar post-receptor mediate adrenocorticotropin release. V2 receptors effects but are less desirable because of inconsistent are present predominantly in the kidney collecting results and significant side effects. Because of the tubules where they mediate free water reabsorp- multiple problems associated with these therapies, tion. In addition, there is now evidence indicating the most frequently employed strategy in SIADH the presence of extrarenal V2 receptors, such as has been to attempt to compensate for the effects of those involved in von Willebrand factor secretion excess AVP secretion by restricting free water (Bernat et al. 1997). Activation of the V2 receptor in intake. Reduction of fluid intake to levels less than renal collecting ducts by circulating AVP leads to insensible losses plus kidney free water excretion an increase in intracellular cAMP by stimulating induces a negative water balance, with subsequent adenylate cyclase activity through Gs protein. This, increases in plasma osmolality and serum [Na+]. in turn, regulates renal free water excretion by Although fluid restriction can effectively counteract shuttling aquaporin-2 (AQP2) water channels from the effect of excess AVP secretion, it does not intracellular vesicles into the apical plasma directly inhibit excess hormone secretion, nor its membrane of the renal collecting duct cells, actions in the kidney. Furthermore, for many thereby increasing water permeability of the patients, long-term fluid restriction can be uncom- membrane and producing an antidiuresis (Nielsen fortable, difficult to maintain, and relatively et al. 1999). ineffective. With the cloning and sequencing of the receptors to which AVP binds, agents that can more directly AVP receptor antagonists antagonize the effects of the hormone at its receptors have now been synthesized. By virtue of Manning and Sawyer first designed peptide these actions, AVP V2 receptor antagonists are antagonists of both the antidiuretic and the promising agents that can block the actions of AVP pressor responses to AVP in the 1970s. Starting Journal of Molecular Endocrinology (2002) 29, 1–9 www.endocrinology.org Downloaded from Bioscientifica.com at 09/28/2021 08:49:37PM via free access Vasopressin V2 receptor antagonists · J G VERBALIS 3 by modifying the highly specific and potent showed a relative V2:V1 selectivity of over antidiuretic peptide desmopressin, a selective 7000-fold in rat and 100-fold in human tissues. peptide V2 receptor agonist, they successfully SR-121463 also potently antagonized AVP- synthesized many vasopressin analogs that effec- stimulated adenylyl cylase activity. VPA-985, tively antagonized the antidiuretic response of AVP another potent selective nonpeptide V2 receptor in vivo (Manning & Sawyer 1991). However, despite antagonist, similarly inhibited binding of AVP to demonstrating potent V2 receptor antagonism in native V2 receptors in membrane isolates from rat animals, many V2 receptor antagonists tested in and dog renal medulla (Chan et al. 1998). In 1997, humans have paradoxically exhibited weak V2 Tahara et al. characterized a nonpeptide combined receptor agonism rather than antagonizing the V1a and V2 receptor antagonist, YM-087. This ff ffi antidiuretic e ects of AVP. Subsequent studies agent demonstrated a high a nity for V1a ff have suggested that this marked species di erence receptors