Vasopressin receptor antagonists initial development efforts on vras during the 1970s focused on peptide analogs derived from the selective v2r agonist desmopressin. They are currently divided into three subtypes, v 1a, v 1b and v 2 and are closely related to oxytocin receptors ot. Binding affinities of oxytocin, vasopressin, and manning. Arginine vasopressin receptors and their nonpeptide inhibitors arginine vasopressin avp is a cyclic nonapeptide fig. Very high affinity vasopressin v 1a and v 2 antagonist. The first nonpeptide vasopressin receptor antagonist vra was recently approved by the united states food and drug administration, and. We recently reported the discovery of a potent, selective, and brainpenetrant v1a receptor antagonist, which was not suitable for full development. During the past decade, the prognosis of patients with pulmonary hypertension ph has improved due to the development of pulmonary arterial vasodilators 1. It is involved in regulation of blood pressure through. Research has revealed the location of action of these nonapeptides through localization of their associated receptors, which include the oxytocin receptor otr and the vasopressin 1a receptor v1ar. Acute hemodynamic effects of conivaptan, a dual v1a and v2.
Vasopressin receptor antagonist an overview sciencedirect topics. A vasopressin receptor antagonist vra is an agent that interferes with action at the vasopressin receptors. Chemical development of the vasopressin receptor 2 antagonist sr121463 1403 fig. Yet, treatment for rightsided heart failure rhf associated with ph has not improved, despite being the most important prognostic factor for chronic rhf 2, 3. Selective, orally active vasopressin v 1a receptor antagonist. Through vasopressin 1a v1a receptors in vascular smooth muscle cells and vasopressin 2 v2 receptors in the renal collecting ducts, vasopressin elicits vasoconstriction and water reabsorption with resultant hyponatremia. Several nonpeptide vasopressin receptor antagonists have been described. The first nonpeptide vasopressin receptor antagonist vra was recently approved by the united states food and drug.
Effects of the nonpeptide v1 vasopressin receptor antagonist. Chemical development of the vasopressin receptor 2. May 10, 2008 argininevasopressin is a hormone that plays an important part in circulatory and water homoeostasis. Development of a human vasopressin v1areceptor antagonist. V2 vasopressin receptor mutations and fluid homeostasis. Pdf vasopressinreceptor antagonists in heart failure. Interfering with avpmediated signaling pharma cologically may be beneficial in heart failure. Vasopressin and diabetes mellitus article pdf available literature.
Selective antagonism of the vasopressin 2 v2 receptor may facili. Vaptans acting on the vasopressin v2 receptors aquaretics have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Vasopressin antagonists in polycystic kidney disease. For example, the intraseptal application of the mixed v1ab receptor antagonist dch25tyretvavp was found to produce anxiolyticlike effects in the elevated plusmaze epm test in rats 14. Vasopressin causes vasoconstriction and renal water resorption via the vasopressin receptor subtypes v1a vascular, v2 renal, and v3 pituitary receptors,1. The drug was administered daily for 12 weeks and was compared with placebo.
Oral vasopressin receptor antagonist tolvaptan in right heart. When lixivaptan, satavaptan or tolvaptan were compared with placebo, they were found to have good effects at elevating serum sodium levels and. Sitespecific mutagenesis was carried out to identify the residues that determine interspecies selectivity for nonpeptide antagonist binding. Apr 22, 2017 mao zl, stalker d, keirns j 2009 pharmacokinetics of conivaptan hydrochloride, a vasopressin v 1a v 2 receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4day openlabel study. V 1a receptors are expressed in the liver, vascular smooth muscle cells, brain and in many other tissues 12, 21, 22. Vasopressin2 receptor antagonist attenuates the ability of. Over the past two decades, various vasopressin receptor antagonists vras have been. In vivo, the compound acted as a specific antagonist of arginine vasopressin avpinduced vasoconstriction. Sep 21, 2003 we used animal models orthologous to the human disorders to test whether a vasopressin v2 receptor vpv2r antagonist, opc31260, would be effective against early or established disease. Arginine vasopressin mediates its actions through three known receptors. Vasopressin antagonists are drugs that bind to vasopressin receptors v1a, v1b and v2 and block the action of vasopressin antidiuretic hormone, adh, which is a hormone released by the pituitary gland. Mechanism of action for vasopressin and v2 receptor antagonists.
Mice genetically deficient in vasopressin v1a and v1b. Vasopressin receptor antagonists and their role in clinical medicine. Opc41061 antagonized 3havp binding to human v2 receptors k i 0. The first nonpeptide vasopressin receptor antagonist was recently. Abstractwe assessed the clinical and pharmacological profile of the orally active v 1 vascular vasopressin avp receptor nonpeptide antagonist sr49059 sr during the osmotic stimulation of avp release in hypertensive patients. The vasopressin v1a receptor v1ar is a gqcoupled receptor that activates phospholipase c and increases cytosolic free calcium. Vasopressin receptor antagonists, heart failure, and.
In 2009, an oral vasopressin v2 receptor antagonist, tolvaptan, was also approved for the treatment of euvolemic and hypervolemic hyponatremia. New drug class nonpeptide argininevasopressin antagonists. Sep 18, 2012 arginine vasopressin avp is a neuropeptide hormone that plays an important role in circulatory and sodium homeostasis, and regulating serum osmolality. This receptor works together with a hormone called vasopressin or antidiuretic hormone adh in the kidneys.
Serotonin receptors involved in vasopressin and oxytocin. Food and drug administration fda approved conivaptan, a combined v 1a and v 2 vasopressin receptor antagonist, for treatment of euvolemic hyponatremia, and in 2006 this approval was extended to patients with hypervolemic hyponatremia. The neuropeptide vasopressin has been implicated in the regulation of social behaviors in animals and humans. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with. Balesd acalifornia national primate research center, university of californiadavis, davis, ca, usa. A vasopressin 1a v1a receptor antagonist, balovaptan has shown the potential to improve social interaction and communication in people with autism spectrum disorder. Oral vasopressin receptor antagonist tolvaptan in right. We examined the use of an orally active vasopressin v 2 receptor antagonist for 30 days to correct and maintain serum sodium concentrations in a population with hyponatremia from various causes e.
In the vasculature, v 1a receptors mediate the pressor actions of avp by a phospholipase cmediated pathway. The oxytocinvasopressin receptor antagonist atosiban delays. Both drugs have potent diuretic effects and are useful for treatment of the syndrome of inappropriate antidiuretic hormone secretion and other states of hyponatremia. The introduction of rat amino acids in position 224, 310, 324, or 337 of the human v1r sequence. Most commonly vras are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or siadh. The vasopressin v2 receptor is found in structures called collecting ducts, which are a series of small tubes that reabsorb water from the kidneys into the bloodstream. Two vasopressin antagonists, tolvaptan oral v2 receptor antagonist144 and conivaptan oral dual v1 and v2 receptor antagonist145147 are currently under clinical evaluation. The effects come about by activation of a specific receptorthe v2vasopressin receptorwhich is expressed on collecting duct cells and on cells of the thick ascending loop of henle of the nephron. Role of vasopressin antagonists american society of. Vasopressin and vasopressin antagonists in heart failure. Existing treatment strategies for rhf associated with ph are restricted to. Tolvaptan, a selective oral vasopressin v2receptor. Vasopressin receptor inhibitors agonists modulators. Vasopressin receptor antagonists and their role in.
Vasopressin causes vasoconstriction and increases reabsorption of water by the kidneys. Effects of sr49059, a new orally active and specific vasopressin v1 receptor antagonist, on vasopressininduced vasoconstriction in humans. Opc21268, an orally effective, nonpeptide vasopressin v1. Vasopressin receptor antagonists vaptans are a new group of nonpeptide drugs which have been used in various clinical conditions with limited success. Therapeutic potential of vasopressin receptor antagonists. Moreover, infusion of an antisense oligodeoxynucleotide to the v1a subtype. Dosing, uses, side effects, interactions, patient handouts, pricing and more from medscape reference. Jan 29, 2018 a vasopressin 1a v1a receptor antagonist, balovaptan has shown the potential to improve social interaction and communication in people with autism spectrum disorder. Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion siadh and disorders of water retention such as congestive heart. The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity vaptans has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vasopressin receptor antagonists kidney international. The affinity of the nonpeptide antagonist opc21268 is greater for the rat v1 arginine vasopressin avp receptor v1r than for the human v1r. The avpr2 gene provides instructions for making a protein known as the vasopressin v2 receptor.
They are currently divided into three subtypes, v 1a, v 1b and v 2 and are closely related to oxytocin receptors ot v 1a is coupled to g q11 proteins and is found at high density on smooth muscle cells. The pharmacological profile and the acute and chronic aquaretic effects of opc41061, a novel nonpeptide human arginine vasopressin avp v2 receptor antagonist, were respectively characterized in hela cells expressing cloned human avp receptors and in conscious male rats. A novel vasopressin receptor antagonist arginine vasopressin, also known as antidiuretic hormone, is a neuropeptide that functions in the maintenance of body water. Vasopressin receptors are a group of gproteincoupled receptors that mediate vasoconstriction, antidiuresis and acth release. Opc41061, a highly potent human vasopressin v2receptor. A single dose, randomized, controlled proofofmechanism. Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients and is associated with considerable morbidity and mortality. Vasopressin v2 receptors v2r, which are found in vascular endothelium and the principal cells of the renal collecting and connecting tubules. Ym087, a vasopressin v1a and v2 receptor antagonist, in dogs with pacinginduced congestive heart failure. Issues related to the differential diagnosis of shock and the use of vasopressors in patients. The first non peptide vasopressin receptor antagonist was recently approved by the. The v 1 receptor antagonist did not block the stimulatory effects of vasopressin, whereas the v 2 receptor antagonist sr121463b decreased afc by 30% in control rats and signi. Plasma glucose levels and renal function in diabetic rats treated with a vasopressin v2 receptor antagonist.
Vasopressin receptor antagonists vaptans are a new group of nonpeptide drugs which have been used in various clinical conditions with. V2vasopressin receptor antagonistsmechanism of effect and. Oxytocin ot and arginine vasopressin avp, as well as synthetic ligands targeting their receptors otr, v1ar, are used in a wide variety of research contexts, but typically their pharmacological properties are determined in only a few species. Vasopressin receptor antagonists vras are drugs that block vasopressin receptors. The pharmacological profile and the acute and chronic aquaretic effects of opc41061, a novel nonpeptide human arginine vasopressin avp v2receptor antagonist, were respectively characterized in hela cells expressing cloned human avp receptors and in conscious male rats. Tolvaptan, a selective oral vasopressin v2 receptor antagonist, for hyponatremia.
Effects of tolvaptan, an oral vasopressin v 2 receptor antagonist, in hyponatremia commentary on schrier rw, gross p, gheorghiade m, et al. Pdf vasopressin receptor antagonists and their role in clinical. Roche said the drugs efficacy has supporting evidence from both human and animal studies that implicate the v1a receptor in mediating and modulating key social behaviors in. Vasopressin receptor antagonist an overview sciencedirect. Most commonly vras are used to treat hyponatremia caused by syndrome of inappropriate antidiuretic hormone secretion siadh, congestive heart failure chf and cirrhosis. Three vasopressin receptor antagonists were considered as a group for their use limitations in the treatment of cirrhosis with ascites. In heart failure, avp worsens heart failure by causing vasoconstriction of arteries and veins, potentially contributing to remodeling of.
In the synthesis of the sulfonyl chloride 1, medicinal chemists started from 3methoxy4. This pathway increases the exocytosis of vesicles containing aquaporin water channels and. The increased apical membrane aquaporin channel density results in. Syrian hamsters mesocricetus auratus have a long history of use as a behavioral and biomedical model for the study of oxytocin and vasopressin.
Vasopressin and vasopressin receptor antagonists ncbi. Ht receptors in the serotonergic regulation of vasopressin and oxytocin secretion. Vasopressin receptor antagonists and their role in clinical. Vasopressin receptor 1a v1ar, or arginine vasopressin receptor 1a officially called avpr1a is one of the three major receptor types for vasopressin avpr1b and avpr2 being the others, and is present throughout the brain, as well as in the periphery in the liver, kidney, and vasculature. A novel vasopressin receptor antagonist request pdf. Table 1 from vasopressinreceptor antagonists in heart. The vanilla clinical trial evaluated balovaptan, an oral selective vasopressin v1a receptor antagonist, in 223 men with autism spectrum disorder asd. The three argininevasopressinreceptor subtypesv1a, v1b, and v2all belong to the large rhodopsinlike gproteincoupled receptor family. Oxytocin ot and vasopressin vp are known modulators of social behaviour across rodents. The vaptans are orally and intravenously active nonpeptide vasopressin receptor antagonists that are in development. Mozavaptan hydrochloride shows 85fold selectivity for v 2 receptor over v 1 receptor ic 50 of 1.
The effect of oxytocin and vasopressin on gi motility has to be further evaluated. However, the actual pharmacological dose of oxytocin in this study had no effect. Selective localization of oxytocin receptors and vasopressin 1a receptors in the human brainstem sara m. This compound selectively antagonized binding to the v1 subtype of the vasopressin receptor in a competitive manner. Infusion of vasopressin receptor antagonists directly into the scn of wildtype mice accelerated their recovery from jet lag, suggesting that this pathway may merit further investigation as a pharmacological target for treating jet lag. Comparison of the distribution of oxytocin and vasopressin. Discovery of balovaptan, a vasopressin 1a receptor antagonist. In a doubleblind crossoverversusplacebo study, 24 untreated stage i or ii essential hypertensive patients 12 whites and 12 blacks received a single 300 mg oral. The phase 2 vanilla clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin v1a receptor antagonist, in 223 men with asd and intelligence quotient.
Jetlag symptoms arise from temporal misalignment between the internal circadian clock and external solar time. Table 1 shows the effects of the argininevasopressinreceptor subtypes in relation to their sites of expression. A phase 2 clinical trial of a vasopressin v1a receptor. The v2 vasopressin receptor mutations and fluid homeostasis. An orally effective, nonpeptide, vasopressin v1 receptor antagonist, opc21268, has been identified. The most important physiologic action of vasopressin is to increase water permeability in the collecting duct of the kidney. Basic adrenergic receptor physiology and the principles, complications, and controversies surrounding use of vasopressors and inotropes for treatment of shock are presented here. Summary arginine vasopressin avp functions in the regulation of plasma osmolarity and blood pressure.
The introduction of rat amino acids in position 224, 310, 324, or 337 of the human v1r sequence dramatically. In the late 1980s, it seemed likely that one such agent, a peptide with v2r antagonist effect in animals, would be successfully developed for use in humans. V1 receptor antagonists in animal models of anxiety. Mar 16, 2006 oxytocin andor vasopressin seem to be regulators of gastric emptying during physiological conditions, since the receptor antagonist atosiban delayed the ger. Development of a human vasopressin v 1a receptor antagonist from an evolutionaryrelated insect neuropeptide. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proofofmechanism study. Its primary role involves regulation of the renal and cardiovascular functions 4. Tolvaptan, a selective oral vasopressin v 2receptor antagonist, for hyponatremia. Arginine vasopressin avp is a neuropeptide hormone that plays an important role in circulatory and sodium homeostasis, and regulating serum osmolality. Anxiolytic and antidepressantlike effects of the non. Conivaptan has demonstrated efficacy in animal models of altered cardiac function and volume overload. After oral administration in conscious rats, the compound also.
The effects of vasopressin antidiuretic hormone to cause water retention and hyponatraemia are related to its action on the kidney. The get1 mice treated with opc31260, a nonpeptide arginine vasopressin v2 receptor antagonist, were alleviated from the cerebral water accumulation and neurologic deficit during the early time. Issues related to the differential diagnosis of shock and the use of vasopressors in patients with septic shock are discussed separately. Excess vasopressin produces fluid retention via a direct. Vasopressin, a neurohypophyseal peptide hormone, is the endogenous agonist at v1a, v1b, and v2 receptors.
Several clinical conditions have been associated with inappropriately elevated levels of avp including heart failure, cirrhosis of the liver and the syndrome of inappropriate secretion of antidiuretic hormone. Commentary on schrier rw, gross p, gheorghiade m, et al. Vasopressin receptor antagonists are a new class of agents that were developed to improve hemodynamics, attenuate disease progression, and improve. The v2 vasopressin receptor mutations and fluid homeostasis, cardiovascular research, volume 51, issue 3. Oxytocin and vasopressin agonists and antagonists as. The longacting somatostatin analogue octreotide and the endothelin et b receptor antagonist a192621 have been reported to have opposing effects in animal models orthologous to human polycystic kidney disease that may be mediated by opposing effects on vasopressin stimulated camp accumulation in the kidney. A single dose, randomized, controlled proofofmechanism study of a novel vasopressin 1a receptor antagonist rg77 in highfunctioning adults with autism spectrum disorder.
Vasopressin v2 receptors v2r, which are found in vascular endothelium and the principal cells of. Fda calls roches autism drug a breakthrough biospace. This 12week phase 2 trial showed no improvement on the primary endpoint srs2 score but did show improvement on the secondary. When lixivaptan, satavaptan or tolvaptan were compared with placebo, they were found to have good effects at elevating serum sodium levels and improvement of ascites. The binding of arginine vasopressin to the vasopressin v2 receptor v2r stimulates a g scoupled protein that activates adenylyl cyclase, in turn causing production of cyclic adenosine monophosphate to activate protein kinase a. Chemical development of the vasopressin receptor 2 antagonist. Opc41061 antagonized 3havp binding to human v2receptors k i 0. Conivaptan is a combined vasopressin receptor antagonist with in vitro binding affinities ki of 6. Both of these agents broadly termed vaptans had clinical trial data demonstrating their efficacy in increasing serum sodium levels as well as increasing the percentage of patients with. In such cases, the vasopressin type 2receptor selective antagonist, tolvaptan, is considered a potent therapy, because the upregulation of vasopressin is associated with the aggravation of the reninangiotensinaldosterone system 12. Discovery of balovaptan, a vasopressin 1a receptor.
The arginine vasopressin v2 receptor antagonists opc31260 and tolvaptan inhibit the development of polycystic kidney disease in cpk mice and in three animal orthologs to human autosomal recessive polycystic kidney disease pck rat, autosomal dominant polycystic kidney disease pkd2. Vasopressin receptor antagonists tocris bioscience. Vasopressin and oxytocin secretion was stimulated by 5. Vasopressin receptor antagonists wiley online library. Effects of tolvaptan, an oral vasopressin v2 receptor.
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