Non-peptide Vasopressin Receptor Antagonists Research Articles

MD simulation-based screening approach identified tolvaptan as a potential inhibitor of Eg5.

We discovered tolvaptan as a new Eg5 inhibitor using molecular dynamics simulation-based virtual screening. The Eg5-monastrol, Eg5-ispinesib, and Eg5-STLC complexes with "closed" L5 conformation obtained in MD simulation were used to generate a combined pharmacophore model, and this model was used during the process of virtual screening. Further, the MD simulation for 1µs showed that the binding of tolvaptan to Eg5 was stable due to the closure of the α2/L5/α3 pocket. Tolvaptan belongs to the class of drugs called vaptans which are non-peptide vasopressin receptor antagonists. Since our virtual search for mitotic inhibitors identified tolvaptan as a potential candidate, we were interested in unraveling its antimitotic mechanism. Tolvaptan bound to purified Eg5-437H with a dissociation constant of 27 ± 3.8µM. Tolvaptan inhibited the growth of HeLa cells through the mitotic block, and around 70% of these mitotic cells exhibited a characteristic monopolar spindle. Tolvaptan bound to goat brain tubulin with a dissociation constant of 103 ± 13µM. The binding location of tolvaptan on tubulin overlapped with that of colchicine, according to molecular docking analysis. The combination of tolvaptan with STLC augmented mitotic bock with monopolar cells, whereas its combination with vinblastine increased mitotic block with bipolar cells. Since tolvaptan is found to have a significant cytotoxic effect on HeLa cells, it can be developed as a prospective anticancer agent either alone or in combination with other antimitotic drugs. Tolvaptan was identified as an inhibitor of Eg5 in a MD simulation-based virtual screening using a combined pharmacophore model.

Vaptans for oedematous and hyponatraemic disorders in childhood: A systematic literature review.

The aim of this study was to systematically review the use of vaptans (nonpeptide vasopressin receptor antagonists) in children. Through a database search (Web of Science, the National Library of Medicine, Excerpta Medica), we identified case series and case reports and extracted clinical and laboratory data. Twenty-six articles, published since 2008, reported on 226 patients. Among 115 children with hyponatraemic (n = 63) and oedematous disorders (n = 52), a 48 hour course of tolvaptan with an initial dose of 0.38 ± 0.27 mg/kg was administered in 106 cases, while intravenous conivaptan was reported in nine cases. An increase (P < .02) in urine output was shown in both oedematous (from 3.2 ± 2.0 to 5.3 ± 6.7mL/kg/day) and hyponatraemic (from 3.0 ± 1.5 to 4.4 ± 2.3mL/kg/day) patients. In these latter, sodium increased from 125 ± 6 to 133 ± 6mmol/L (P < .0001). The increase in sodium level correlated with its basal value, but not with the administered vaptan dose. Among 111 children undergoing cardiac surgery, after tolvaptan 0.21 ± 0.01 mg/kg/day, mostly combined with conventional diuretics, an increase in diuresis by 41 ± 4% was seen within 24 hours (P < .0001). Similarly, a single add-on dose of tolvaptan 0.45 mg/kg allowed a reduced additional intravenous furosemide administration (0.26 ± 0.23 vs 0.62 ± 0.48 mg/kg, P < .005). Side effects were rarely reported, and included excessive thirst and xerostomia in seven, skin rash in one and elevated aminotransferases in one patient(s). Vaptans appear to be safe for oedematous and hyponatraemic disorders also in children. Although they increase diuresis and natraemia, no superiority to traditional diuretics and sodium supplements has been demonstrated. Reported side effects are rare and non-serious.

Effectiveness of Tolvaptan Treatment in Hyponatremic Patients

Objective: Non-peptide vasopressin receptor antagonists (vaptans) are effective at increasing sodium in euvolemic and hypervolemic states and appear safe. We aimed to evaluate the efficacy of tolvaptan in euvolemic or hypervolemic hyponatremic patients. Methods: The study included 9 hyponatremic (serum sodium level &amp;lt;125 mmol/L) patients. Serum potassium levels of all patients were normal and there was no acid-base disturbance. Patients with hypovolemic status and hepatic dysfunction were excluded from the study. Clinical and laboratory data of patients were obtained before and after tolvaptan (7.5 mg/day) treatment. Results: The median age of patients (6 females, 3 males) was 66.3 years (range, 56-82). The mean sodium levels before tolvaptan treatment were 120.5 mEq/L (SD 2.2, range, 116-124). The mean sodium levels increased significantly to 132.6±4.0 mEq/L (range, 125-140) after tolvaptan treatment at 2.7±1.3 days (range, 2-6) (p&amp;lt;0.001). Hyponatremia did not recur after tolvaptan treatment. We did not observe serious adverse event related with tolvaptan treatment. Conclusion: Hyponatremia was a common problem, and tolvaptan can treat hyponatremia effectively and safely in patients with euvolemic or hypervolemic hyponatremia.

UPLC/MS-MS assay development for estimation of mozavaptan in plasma and its pharmacokinetic study in rats.

Mozavaptan is a nonpeptide vasopressin receptor antagonist approved for the treatment of ectopic antidiuretic hormone secretion syndrome. A simple, rapid and fully validated UPLC/MS-MS method was developed for the quantitation of mozavaptan in rat plasma. The chromatographic separation was conducted on an Acquity UPLC BEH™ C18 column with an optimum mobile phase of 10mM ammonium acetate buffer and 0.1% formic acid in acetonitrile (30:70 v/v) at a flow rate of 0.3ml/min. The multiple reaction monitoring transitions were performed at m/z 428.16→119.03 for mozavaptan and m/z 237.06→179.10 for carbamazepine (internal standard). The method was effectively applied for the determination of mozavaptan pharmacokinetic parameters after the oral administration of 3mg/kg mozavaptan in rats.

Pathophysiology, Diagnosis and Clinical Management of Hepatorenal Syndrome: From Classic to New Drugs

Advanced cirrhosis is frequently associated with renal dysfunction. Hepatorenal syndrome (HRS) is characterized by the occurrence of kidney injury in cirrhotic patients in the absence of other identifiable causes. HRS is classified in 2 different types. Type 1 is characterized by acute renal failure and rapid functional deterioration of other organs, usually related to a precipitating event. Type 2 is characterized by slowly progressive renal failure and refractory ascites. Advanced liver disease induces the progression of hemodynamic alterations such as arterial vasodilation of splanchnic circulation and impairment of cardiac function. The resulting ineffective circulating blood volume promotes the activation of both the renin-angiotensin-aldosterone and sympathetic nervous system, by an increase of antidiuretic hormone activity, in an attempt to restore volemia. Despite fluid retention, ascites and dilutional hyponatremia, renal function is often initially preserved by renal production of vasodilators. However, further insults can lead to an imbalance between systemic vasoconstriction and local renal vasodilation, resulting in progressive renal failure. Over the last decade, clinical strategies to prevent HRS have been improved by a better understanding of the natural history of renal failure in cirrhosis, resulting in a reduction of HRS prevalence in cirrhotic patients. Vasoconstrictor drugs may improve renal function, but the effect on mortality has not yet been established. Vaptans, nonpeptide vasopressin receptor antagonists, may also reduce hyponatraemia and ascites, even if the clinical effects in HRS remain unknown. This review updates the pathophysiology, diagnosis and management of HRS.

Therapeutic Potential of Vasopressin-Receptor Antagonists in Heart Failure

Arginine vasopressin (AVP) is a 9-amino acid peptide that is secreted from the posterior pituitary in response to high plasma osmolality and hypotension. AVP has important roles in circulatory and water homoeostasis, which are mediated by oxytocin receptors and by AVP receptor subtypes: V(1a) (mainly vascular), V(1b) (pituitary), and V(2) (renal). Vaptans are orally and intravenously active nonpeptide vasopressin-receptor antagonists. Recently, subtype-selective nonpeptide vasopressin-receptor agonists have been developed. A selective V(1a)-receptor antagonist, relcovaptan, has shown initial positive results in the treatment of Raynaud's disease, dysmenorrhea, and tocolysis. A selective V(1b)-receptor antagonist, nelivaptan, has beneficial effects in the treatment of psychiatric disorders. Selective V2-receptor antagonists including mozavaptan, lixivaptan, satavaptan, and tolvaptan induce highly hypotonic diuresis without substantially affecting the excretion of electrolytes. A nonselective V(1a)/V(2)-receptor antagonist, conivaptan, is used in the treatment for euvolaemic or hypervolemic hyponatremia. Recent basic and clinical studies have shown that AVP-receptor antagonists, especially V2-receptor antagonists, may have therapeutic potential for heart failure. This review presents current information about AVP and its antagonists.

Exploring the Ligand Recognition Properties of the Human Vasopressin V1a Receptor Using QSAR and Molecular Modeling Studies

Vaptans are compounds that act as non-peptide vasopressin receptor antagonists. These compounds have diverse chemical structures. In this study, we used a combined approach of protein folding, molecular dynamics simulations, docking, and quantitative structure-activity relationship (QSAR) to elucidate the detailed interaction of the vasopressin receptor V1a (V1aR) with some of its blockers (134). QSAR studies were performed using MLR analysis and were gathered into one group to perform an artificial neural network (ANN) analysis. For each molecule, 1481 molecular descriptors were calculated. Additionally, 15 quantum chemical descriptors were calculated. The final equation was developed by choosing the optimal combination of descriptors after removing the outliers. Molecular modeling enabled us to obtain a reliable tridimensional model of V1aR. The docking results indicated that the great majority of ligands reach the binding site under π-π, π-cation, and hydrophobic interactions. The QSAR studies demonstrated that the heteroatoms N and O are important for ligand recognition, which could explain the structural diversity of ligands that reach V1aR.

The hyponatremias

Introduction: Plasma sodium concentrations are commonly measured in hospitalized patients. In our department, hypernatremia (defined as a serum sodium &lt; 135 mmol/L) is usually an incidental finding. More rarely, however, clinical manifestations of hypernatremia occur. Symptoms depend on the magnitude and rapidity of onset of the hypernatremia. When acute, severe hyponatremia develops, brain edema may occur. Considerable morbidity and mortality can be associated with hyponatremic encephalopathy per se. Moreover, rapid correction of hyponatremia also carries a risk of neurological damage related to the osmotic demyelination syndromes. This review focuses on the epidemiology, pathophysiology, and therapy of hyponatremia. Materials and methods: We carried out a search of the literature in Medline, the Cochrane Library and Clinical Evidence using the search terms hypernatremia and sodium. Conclusions: Hyponatremia is the most common electrolyte disorder encountered in clinical practice, occurring in approximately 15% to 30% of hospitalized patients, and it is not uncommon in outpatients. When faced with a hyponatremic patient, the physician has to identify the cause, treat the defect, and take care of the patient, bearing in mind that hypernatremia and its correction are associated with significant morbidity and mortality. Hyponatremic encephalopathy following acute hypernatremia is well known to be a potentially life-threatening condition, especially in patients with concomitant diseases. In contrast, chronic hypernatremia is more common, and it is often considered to be a laboratory abnormality devoid of clinical consequences. Paradoxically, however, this is just the setting in which rapid correction of plasma sodium levels can cause severe neurologic defects and death. Despite substantial progress in understanding the pathophysiology of brain damage related to hyponatremia and its treatment, optimal, safe therapies have not been well defined yet. The imminent availability of aquaretic nonpeptide arginine vasopressin receptor antagonists could provide new insights into this field. However, because of their unique effects, i.e., selective increase of solute-free water excretion by the kidney, this new class of drugs cannot be used in patients with hypovolemic hyponatremia.

Vasopressin-2 Receptor Antagonist Attenuates the Ability of the Lungs to Clear Edema in an Experimental Model

In the last two decades, the role of the alveolar active sodium transport was extensively studied and was found to play a crucial role in regulating alveolar fluid clearance (AFC), and thus in keeping the airspaces free of edema. The recent development of highly selective nonpeptide vasopressin-receptor antagonists gives us a rare chance to explore the role of vasopressin in the pathogenesis of lung edema. Therefore, the present study examined the involvement of vasopressin in modulating the ability of the lung to clear edema. Vasopressin enhanced the rate of lung edema clearance by 30% as compared with untreated control rats (from 0.49 ± 0.02 to 0.64 ± 0.02 ml/h), whereas V(2) receptor antagonists significantly decreased the ability of the lung to clear water (from 0.64 ± 0.02 to 0.31 ± 0.06 ml/h; P < 0.0001). In contrast, V(1) receptor antagonist did not change the rate of AFC. The administration of ouabain (a Na,K-ATPase inhibitor) and amiloride (a Na(+) channel blocker) inhibited the stimulatory effects of vasopressin (from 0.64 ± 0.02 to 0.22 ± 0.02 ml/h [P < 0.0001] and from 0.64 ± 0.017 to 0.23 ± 0.02 ml/h [P < 0.0001], respectively). Vasopressin significantly increased Na,K-ATPase protein abundance in the basolateral membranes of the alveolar epithelial cells via V(2) receptor activation. We report a novel role of the vasopressin pathway in AFC. This observation indicates a beneficial role of vasopressin in AFC by up-regulating active sodium transport.

Vaptans: A new option in the management of hyponatremia

Arginine vasopressin (AVP) plays an important role in water and sodium homeostasis. It acts via three receptor subtypes—V1a, V1b, and V2—distributed widely throughout the body. Vaptans are nonpeptide vasopressin receptor antagonists (VRA). By property of aquaresis, VRAs offer a novel therapy of water retention. Conivaptan is a V1a/V2 nonselective VRA approved for euvolemic and hypervolemic hyponatremia. Tolvaptan is the first oral VRA. Other potential uses of this new class of drugs include congestive heart failure (CHF), cirrhosis of liver, syndrome of inappropriate secretion of antidiuretic hormone, polycystic kidney disease, and so on. These novel drugs score over diuretics as they are not associated with electrolyte abnormalities. Though much remains to be elucidated before the VRAs are applied clinically, the future holds much promise.

Vasopressin-Receptor Antagonists

Despite a crucial role in body fluid homeostasis, elevated vasopressin levels can also be pathological in conditions such as congestive heart failure, liver cirrhosis and the syndrome of inappropriate antidiuretic hormone secretion. The result of elevated vasopressin is renal water retention and hyponatremia, a low serum sodium concentration. Hyponatremia is associated with excess morbidity and mortality. Nonpeptide vasopressin-receptor antagonists represent a new drug class of small molecules that competitively inhibit one or more of the vasopressin receptors. There are three vasopressin receptors in humans, including V1a, V1b and V2. Selective V2- and combined V1a/V2-receptor antagonists have been developed for the treatment of hyponatremia resulting from congestive heart failure, liver cirrhosis and the syndrome of inappropriate antidiuretic hormone secretion. Two nonpeptide vasopressin-receptor antagonists, conivaptan and tolvaptan, have recently been approved by American and European drug authorities for clinical use. This article aims to provide a succinct and clinical update on nonpeptide vasopressin-receptor antagonists, including their mechanism of action, performance in randomized clinical trials and current clinical status.

Vasopressinantagonisten

As vasopressin receptors (V1a, V1b, V2) are found in many different tissues, vasopressin antagonists may benefit the treatment of numerous disorders. Effects of vasopressin via V1a and V2 receptors are closely implicated in a variety of water-retaining and cardiovascular diseases, including heart failure, hyponatraemia, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. From the series of non-peptide vasopressin receptor antagonists (vaptans), conivaptan is the only compound, which has been approved by the FDA for the treatment of euvolaemic and hypervolaemic hyponatraemia so far. For further indications such as congenital heart failure, ongoing studies are promising. Based on data from in vitro studies as well as preclinical and clinical trials also other indications for vasopressin receptor antagonists besides hyponatraemia and heart failure are to be expected.

When Is It Appropriate to Use Vasopressin Receptor Antagonists?

Hyponatremia is a common and challenging disorder. The mainstays of treatment until recently were water restriction and hypertonic saline. The first nonpeptide vasopressin receptor antagonist (VRA) is now approved by the US Food and Drug Administration for use in patients with euvolemic and hypervolemic hyponatremia. VRA induce urinary dilution with an aquaresis that leads to an increase in serum sodium concentration. In patients with heart failure, VRA modestly improve congestive symptoms but have no effect on short- or long-term mortality. Long-term effects have not been extensively studied, but serious adverse effects of VRA are rare, and the rate of rise in serum sodium that they produce seems unlikely to lead to osmotic demyelination. Beneficial effects beyond changing serum tonicity and alternative uses, such as in polycystic kidney disease, need further exploration. This commentary discusses the current and potential indications for use of VRA.

Vasopressin and Vasopressin Receptor Antagonists

Vasopressin, a neurohypophyseal peptide hormone, is the endogenous agonist at V1a, V1b, and V2 receptors. The most important physiological function of vasopressin is the maintenance of water homeostasis through interaction with V2 receptors in the kidney. Vasopressin binds to V2 receptor and increases the number of aquaporin-2 at the apical plasma membrane of collecting duct principal cells. That induces high water permeability across the membrane. Several non-peptide vasopressin receptor antagonists have been developed and are being studied primarily for treating conditions characterized by hyponatremia and fluid overload. Further studies are needed to determine how they are best used in these situations.

Conivaptan: New treatment for hyponatremia

The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, adverse effects and toxicities, drug interactions, dosage and administration, and safety issues related to the use of conivaptan are discussed. Conivaptan hydrochloride is a nonpeptide, V1A and V2 vasopressin-receptor antagonist. It is available as an i.v. formulation in 4-mL ampules containing 20 mg of conivaptan hydrochloride. The drug is active both orally and i.v. Conivaptan injection is approved for the treatment of euvolemic hyponatremia in hospitalized patients. Three double-blind, placebo-controlled, randomized, multicenter studies have been conducted in the United States and internationally. The studies used various dosing regimens for conivaptan but maintained the same efficacy endpoints. Each study showed conivaptan to be effective in increasing serum sodium and in water clearance. Conivaptan is being evaluated in the treatment of acute decompensated heart failure and chronic heart failure, but the safety of this drug has not been fully established. The drug has been generally well tolerated in clinical trials with both oral and i.v. administration. The approved dosing regimen consists of a 20-mg i.v. loading dose administered over 30 minutes, followed by a continuous infusion of 20 mg administered over 24 hours. Clinical studies evaluating conivaptan have been short term; longer-term effects of hemodynamic parameters are unknown. Conivaptan, the first vasopressin antagonist approved for the treatment of euvolemic hyponatremia, has a unique mechanism of action that results in free-water excretion and offers a new option for the treatment of resistant hyponatremia in the acute setting when patients have not responded to standard management.

Vasopressin receptor antagonists

The first non-peptide vasopressin receptor antagonist (VRA) was recently approved by the United States Food and Drug Administration, and several others are now in late stages of clinical development. Phase 3 trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. Although tachyphylaxis to the hydro-osmotic effect of these agents does not appear to occur, their use is accompanied by an increase in thirst, and they do not always eliminate altogether the need for water restriction during treatment of hyponatremia. Experience with use of these agents for treatment of acute, severe, life-threatening hyponatremia as well as chronic hyponatremia is limited. Further studies are needed to determine how they are best used in these situations, but the risk of overly rapid correction of hyponatremia seems low. Results of long-term trials to determine the ability of VRAs to reduce morbidity or mortality in congestive heart failure or to slow the progression of polycystic kidney disease are awaited with great interest.

Vasopressin receptor antagonists in the management of acute heart failure

Vasopressin is a potent vasoconstrictor and plays a significant role in the regulation of volume homeostasis. Several non-peptide vasopressin receptor antagonists (vaptans) have emerged as promising drugs in the management of acute heart failure. Results of early trials with tolvaptan (selective vasopressin subtype 2 receptor antagonist) and conivaptan (dual vasopressin subtypes 1a and 2 receptor antagonist) have demonstrated improvement in the fluid status, osmotic balance and haemodynamic profile in patients with heart failure presenting with signs and symptoms of decompensation. Nevertheless, their comparative long-term safety and efficacy remains to be determined in large-scale clinical trials.

Pharmacologic properties of YM218, a novel, potent, nonpeptide vasopressin V 1A receptor-selective antagonist

The pharmacologic profile of YM218, ( Z)-4′-{4,4-difluoro-5-[2-oxo-2-(4-piperidinopiperidino)ethylidene]-2,3,4,5-tetrahydro-1 H-1-benzoazepine-1-carbonyl}-2-methyl-3-furanilide hemifumarate, a newly synthesized, nonpeptide vasopressin (AVP) receptor antagonist, was investigated using several in vitro and in vivo methods. YM218 exhibited high affinity for V 1A receptors isolated from rat liver, with a K i value of 0.50 nM. In contrast, YM218 exhibited much lower affinity for rat pituitary V 1B, kidney V 2, and uterus oxytocin receptors, with K i values of 1510 nM, 72.2 nM, and 150 nM, respectively. In vivo studies revealed that YM218 dose-dependently inhibited pressor response to exogenous AVP in pithed rats (intravenous) and in conscious normotensive rats (intravenous or oral) with a long duration of action (>8 h at 3 mg/kg, p.o.). In contrast, oral administration of YM218 did not increase urine excretion in conscious rats. These results demonstrate that YM218 is a potent nonpeptide AVP V 1A receptor-selective antagonist that will be useful in future studies to help clarify the physiologic and pathophysiologic roles of AVP.

Bridged Bicyclic Vasopressin Receptor Antagonists with V2‐Selective or Dual V1a/V2 Activity.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Bridged bicyclic vasopressin receptor antagonists with V 2-Selective or dual V 1a/V 2 activity

The synthesis and biological testing of a novel series of nonpeptide vasopressin receptor antagonists, containing a bridged bicyclic nucleus, are reported. Variation of substituents (R 1–R 3) in general formula 3, and the configuration of the stereocenter, resulted in potent V 2-selective (e.g., 4) and balanced dual V 1a/V 2 (e.g., 10) compounds. Data from receptor binding, cell-based functional, and in vivo assays are presented.