Vasopressin V2 receptor ( IC50 = 14 nM ); Vasopressin V1 receptor ( IC50 = 1.2 μM )

In vitro activity: Mozavaptan (OPC-31260) is approximately 100 times more selective for V2 receptors and inhibits AVP binding to rat liver (V1 receptor) and kidney (V2 receptor) plasma membranes in a competitive manner. Rat kidney has a [3H]-AVP K_d value of 1.38 nM, whereas rat liver has a value of 1.1 nM. In rat liver and kidney, mozavaptan significantly lowers the [3H]-AVP K_d (K_d of 2.47 nM and 5.51 nM for V1 receptor at 0.3 μM and 1 μM, respectively; K_d of 2.4 nM and 4.03 nM for V2 receptor at 0.3 μM and 1 μM, respectively)[1].

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OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2. OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 +/- 0.2 x 10(-6) M and 1.4 +/- 0.2 x 10(-8) M, respectively [1].

Mozavaptan (OPC-31260; 1-30 mg/kg; oral administration; hydrated conscious rats) treatment increases urine flow and lowers urine osmolality in a dose-dependent manner[1].
Mozavaptan (OPC-31260; 10-100 μg/kg; intravenous injection; male Sprague-Dawley rats) treatment dose-dependently blocks the antidiuretic effect of exogenously administered arginine vasopressin (AVP) in rats anesthetized with alcohol and loaded with water[1].

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OPC-31260 at doses of 10 to 100 micrograms kg-1, i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4. After oral administration at doses of 1 to 30 mg kg-1 in normal conscious rats, OPC-31260 dose-dependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5. The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention [1].

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Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life[2].

To determine binding kinetic constants, liver or kidney plasma membranes are incubated with increasing concentrations of [3H]-AVP with or without excess (1 μM) unlabelled AVP to obtain a saturation curve. Mozavaptan interacts either noncompetitively or competitively, as determined by examining the saturation binding of [3H]-AVP in liver membranes at concentrations of 0.3 μM and 1 μM, and in kidney membranes at concentrations of 3 nM and 10 nM. The Scatchard method is used to plot the data on the saturation curve, and regression analysis is used to fit the data.

Dissolved in 3% ethanol (v/v), 1.67% glucose (w/v) and 0.3% NaCl (w/v); 10, 30, 100μg/kg;
i.v. injection;
Male Sprague-Dawley rats.

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This open-label, multicenter study protocol was approved by the Institutional Review Board of each participating medical institution prior to its inception; written informed consent was obtained from all patients.
Recruited were inpatients aged 20 to <75 years who had malignant tumors that might cause ectopic ADH syndrome as well as the diagnostic criteria of ectopic ADH syndrome as defined by Bartter and Schwartz such as serum sodium concentration ≤124 mEq/l, persistent urinary sodium excretion, normal renal, adrenal, and thyroid function, and no evidence of edema or dehydration.
Following a ≤2-day placebo administration period during which baseline data were collected, patients were given orally mozavaptan (single 30 mg tablet) once daily for 7 days, or where this was difficult, 3 days was allowed. Fluid restriction was used throughout the study period only for patients in whom it had already begun. Treatment of hyponatremia with demeclocycline, lithium chloride, or urea was not permitted.
The primary endpoint was serum sodium concentration. Blood samples were collected immediately before dosing on each test day. Clinical symptoms associated with hyponatremia such as anorexia, nausea/vomiting, headache, and CNS symptoms were recorded. Urine volume, urinary osmolality, urinary electrolyte (sodium, potassium, chloride) excretion, serum electrolyte (potassium, chloride) concentration, serum osmolality, and plasma ADH concentration were measured. New medical problems or exacerbations of those already existing were reported as adverse events.
In each case, the serum sodium level after the final administration of the study drug was compared with baseline value. The patients are divided into three groups: (i) the serum sodium level is improved to normal range; (ii) the level is still low, but increase is ≥6 mEq/l and (iii) the level is still low, and increase is <6 mEq/l. And mean sodium concentration after the final administration of the study drug was compared with that of baseline value by paired t-test [2].

At baseline and at the end of study, mean serum sodium concentration was 122.8 ± 6.7 and 133.3 ± 8.3 mEq/l, respectively, a statistically significant difference (P = 0.002; Fig. 1). Serum sodium concentration increased at 24 h after the first administration of mozavaptan and remained elevated ≤24 h after administration for 7 days. Serum osmolality gradually increased starting from 24 h after first administration till the study end. Cumulative urine volume over 24 h increased on the first treatment day, whereas urine osmolality decreased in the first two treatment days. [2]

mouse LDLo oral 1500 mg/kg SENSE ORGANS AND SPECIAL SENSES: PTOSIS: EYE; BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Biological and Pharmaceutical Bulletin., 23(182), 2000 [PMID:10706381]

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A total of 16 patients were evaluated for the serum sodium level. The serum sodium level was improved to normal range in eight patients, still below normal range but increased by at least 6 mEq/l in four patients and increased by <6 mEq/l in four patients (Table 1).
Symptoms associated with ectopic ADH syndrome such as anorexia, nausea/vomiting, headache and CNS symptoms improved or disappeared in seven of eight patients who had at least one of these symptoms at baseline. By symptom, anorexia disappeared in three and improved in two among eight patients who had the symptom at baseline, whereas nausea/vomiting, headache and CNS symptoms disappeared by the completion of treatment in all patients who had at least one of the symptoms at baseline. On the other hand, however, new anorexia and headache developed in one patient each.
Although some patients showed slight increases or decreases of plasma ADH concentration after receiving mozavaptan, overall there were no obvious changes.
There were 35 adverse events in 11 of the 16 patients; none was serious. The most common adverse event was dry mouth developing in five patients. Fifteen adverse drug reactions occurred in six patients (dry mouth, n = 5; increased blood potassium, n = 2; malaise, increased AST, increased ALT, decreased blood calcium, increased blood lactate dehydrogenase, increased blood urea, decreased appetite and nocturia, n = 1 each).
One patient was withdrawn after administration of the study drug for 3 days because of anorexia. After completion of administration of mozavaptan, one cancer-related death occurred 30 days post-treatment (ID 1 in Table 1); the patient had small cell lung cancer, and had myasthenia gravis, diabetes, pneumonia and hypertension. Chemotherapy (carboplatin and etoposide) was given from 146 to 144 days before treatment with mozavaptan, which reduced the tumor size and improved SIADH. However, the chemotherapy was terminated due to marked myelosuppression, and then this led to marked tumor growth. The serum sodium concentration was 132 mEq/l 29 days before the mozavaptan treatment, but gradually decreased to 119 mEq/l 14 days before treatment. At that time, the patient's condition did not permit chemotherapy, and mozavaptan therapy was performed. Although mozavaptan was effective, the condition became worse due to rapid tumor progression. The patient died 30 days after completion of the mozavaptan therapy, and the autopsy demonstrated direct invasion to heart and thoracic vertebra, indicating that the patient had died of cancer. No other serious adverse events were reported.[2]

[1]. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br J Pharmacol. 1992 Apr;105(4):787-91.

[2]. Clinical implication of the antidiuretic hormone (ADH) receptor antagonist mozavaptan hydrochloride in patients with ectopic ADH syndrome. Jpn J Clin Oncol. 2011 Jan;41(1):148-52.

Mozavaptan is a member of benzamides. It has a role as an aquaretic.

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On the basis of these results, mozavaptan (Physuline®) was approved in Japan as an orphan drug for the treatment of ectopic ADH syndrome, in 2006. It is worth noting that until now demeclocycline, lithium chloride or urea was reported effective for the ectopic ADH syndrome, although clinical experiences revealed that the effects of these drugs are limited.
In the USA and EU, there are two V2R antagonists available on the market—conivaptan (injection formulation) and tolvaptan (oral tablet). Conivaptan, a dual V1a receptor and V2R antagonist, is marketed in the USA with the indication of ‘treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients’. Tolvaptan, which by structural modification has a higher affinity for the V2R than does its parent drug, mozavaptan, is marketed in the USA with the indication of ‘treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure, cirrhosis and SIADH’ and in the EU with the indication of ‘treatment of adult patients with hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH)’. Mozavaptan is currently the only approved drug available for treatment of patients with ectopic ADH syndrome in Japan but is neither approved nor under development outside Japan.
During the 43 months following its launch, 100 patients have been treated with the drug. On the basis of the post-marketing drug use results survey, overall clinical effects of the drug have been found similar to those of the clinical trial. Mozavaptan provides two important contributions for the treatment of ectopic ADH syndrome. First, short-term treatment with mozavaptan may allow hyponatremic patients who might otherwise be contraindicated to receive aggressive cancer chemotherapy with platinum-containing drugs. Second, mozavaptan may free patients from strict fluid-intake restrictions and thereby improve their quality of life. Thus, mozavaptan provides new treatment options for aggressive chemotherapy as well as for palliative care in patients with ectopic ADH syndrome. [2]

C27H29N3O2

427.54

427.225

C, 75.85; H, 6.84; N, 9.83; O, 7.48

137975-06-5

Mozavaptan hydrochloride; 138470-70-9

119369

White to off-white solid powder

1.2±0.1 g/cm3

543.0±50.0 °C at 760 mmHg

282.2±30.1 °C

0.0±1.5 mmHg at 25°C

1.647

3.83

1

3

4

32

643

0

O=C(C1C([H])=C([H])C(=C([H])C=1[H])N([H])C(C1=C([H])C([H])=C([H])C([H])=C1C([H])([H])[H])=O)N1C2=C([H])C([H])=C([H])C([H])=C2C([H])(C([H])([H])C([H])([H])C1([H])[H])N(C([H])([H])[H])C([H])([H])[H]

WRNXUQJJCIZICJ-UHFFFAOYSA-N

InChI=1S/C27H29N3O2/c1-19-9-4-5-10-22(19)26(31)28-21-16-14-20(15-17-21)27(32)30-18-8-13-24(29(2)3)23-11-6-7-12-25(23)30/h4-7,9-12,14-17,24H,8,13,18H2,1-3H3,(H,28,31)

N-[4-[5-(dimethylamino)-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl]phenyl]-2-methylbenzamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)