Vasopressin V2 receptor ( IC50 = 14 nM ); Vasopressin V1 receptor ( IC50 = 1.2 μM )
Vasopressin V2 receptor (Ki = 1.2 nM, rat; IC50 = 2.5 nM for cAMP inhibition) [1]
- Vasopressin V1a receptor (Ki = 180 nM, rat; >150-fold lower affinity than V2) [1]

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].

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Mozavaptan (OPC-31260) is an orally active, non-peptide antagonist of the vasopressin V2 receptor, with high selectivity for V2 over V1a receptors [1]
- In rat V2 receptor-expressing CHO cells, Mozavaptan competitively displaced [3H]-AVP binding and inhibited AVP-induced cAMP accumulation, with an IC50 of 2.5 nM [1]
- In rat renal collecting duct cells, Mozavaptan (1-100 nM) blocked AVP-mediated water reabsorption by 55-75% via inhibiting aquaporin 2 (AQP2) translocation, without affecting sodium transport [1]
- It showed negligible activity on V1a receptors at concentrations up to 100 nM, confirming V2-selective action [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].

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In normal rats, oral Mozavaptan (1-10 mg/kg) induced dose-dependent aquaresis (water-specific diuresis), increasing urine output by 2.1-3.3 fold within 6 hours and normalizing plasma osmolality [1]
- In rats with vasopressin-induced water retention, Mozavaptan (3 mg/kg, p.o.) reversed antidiuresis, increasing urine volume by 2.8 fold and reducing urine osmolality by 60% [1]
- In patients with ectopic ADH syndrome (n=11), oral Mozavaptan (15-60 mg/day for 7-14 days) increased serum sodium concentration from 125.3 ± 3.2 mEq/L to 136.5 ± 2.8 mEq/L, with a response rate of 90.9% [2]
- In the clinical study, Mozavaptan improved symptoms of hyponatremia (lethargy, confusion) without significant changes in potassium levels or blood pressure [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.

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Vasopressin V2/V1a receptor binding assay: Membrane preparations from rat V2/V1a receptor-expressing cells were incubated with [3H]-AVP (0.5 nM) and Mozavaptan (0.01-10000 nM) at 25°C for 60 minutes. Non-specific binding was determined with excess unlabeled AVP. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [1]
- V2 receptor cAMP inhibition assay: V2 receptor-expressing CHO cells were preincubated with IBMX (phosphodiesterase inhibitor) and Mozavaptan (0.1-100 nM) for 20 minutes, then stimulated with AVP (10 nM) for 30 minutes. Intracellular cAMP was extracted and quantified by radioimmunoassay to determine IC50 values [1]

Renal collecting duct water reabsorption assay: Rat renal collecting duct cells were cultured on permeable supports, pretreated with Mozavaptan (1-100 nM) for 30 minutes, then exposed to AVP (1 nM). Transepithelial water flux was measured by monitoring changes in medium volume over 2 hours [1]
- AQP2 translocation assay: Rat renal collecting duct cells were treated with Mozavaptan (10-100 nM) and AVP (1 nM) for 45 minutes. Cells were fixed, immunostained for AQP2, and analyzed by fluorescence microscopy to assess apical membrane localization [1]

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].

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Normal rat aquaresis assay: Male Wistar rats (200-250 g) were administered Mozavaptan (1, 3, 10 mg/kg) via oral gavage. Urine volume, urine osmolality, and plasma osmolality were measured at 2, 4, 6, and 24 hours post-administration [1]
- Vasopressin-induced water retention rat model: Rats were injected subcutaneously with vasopressin (0.1 U/kg) to induce antidiuresis. One hour later, Mozavaptan (3 mg/kg) suspended in 0.5% CMC-Na was administered orally. Urine output and osmolality were monitored for 6 hours [1]

At baseline and at the end of the study, the mean serum sodium concentrations were 122.8 ± 6.7 mEq/L and 133.3 ± 8.3 mEq/L, respectively, which were statistically significant (P = 0.002; Figure 1). Serum sodium concentrations increased 24 hours after the first administration of mozavatan and remained elevated for 7 days within ≤24 hours after administration. Serum osmolality gradually increased from 24 hours after the first administration until the end of the study. Cumulative urine volume increased 24 hours after the first administration, while urine osmolality decreased during the first two days of administration. [2] Oral bioavailability: Approximately 70% after oral administration in rats [1] - Elimination half-life: 3–4 hours in rats [1]

Mice were orally administered LDLo 1500 mg/kg. Sensory organs and special senses: ptosis; Behavior: somnolence (reduced overall activity). Journal of Biology and Pharmaceutical Sciences, 23(182), 2000 [PMID:10706381]

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Serum sodium levels were assessed in 16 patients. Serum sodium levels returned to normal in 8 patients, serum sodium levels remained below normal but increased by at least 6 mEq/L in 4 patients, and serum sodium levels increased by less than 6 mEq/L in 4 patients (Table 1).
Of the 8 patients who had at least one ectopic ADH syndrome-related symptom at baseline (such as anorexia, nausea/vomiting, headache, and central nervous system symptoms), these symptoms improved or disappeared in 7 patients. By symptom analysis, of the 8 patients with anorexia at baseline, anorexia disappeared in 3 patients and improved in 2 patients; while in patients who had at least one nausea/vomiting, headache, and central nervous system symptoms at baseline, these symptoms disappeared after treatment. However, one patient developed new anorexia, and another developed new headache. Although some patients experienced slight increases or decreases in plasma antidiuretic hormone (ADH) levels after mozavatan treatment, no significant changes were observed overall. Of the 16 patients, 11 experienced 35 adverse events, all of which were minor. The most common adverse event was dry mouth in 5 patients. A total of 15 adverse drug reactions occurred in 6 patients (dry mouth, n=5; elevated serum potassium, n=2; malaise, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), decreased serum calcium, elevated serum lactate dehydrogenase, elevated blood urea nitrogen, decreased appetite, and nocturia, 1 case each). One patient withdrew from the study due to anorexia after 3 days of treatment with the study drug. After completion of mozavatan treatment, one patient died 30 days later from cancer-related illness (ID 1 in Table 1); this patient had small cell lung cancer, accompanied by myasthenia gravis, diabetes, pneumonia, and hypertension. 146 to 144 days prior to mozavatan treatment, the patient received chemotherapy with carboplatin and etoposide, which shrunk the tumor and improved syndrome of inappropriate antidiuretic hormone secretion (SIADH). However, chemotherapy was discontinued due to significant myelosuppression, subsequently leading to rapid tumor growth. Twenty-nine days before mozavatan treatment, the patient's serum sodium concentration was 132 mEq/L, but it gradually decreased to 119 mEq/L 14 days prior to treatment. At this point, the patient's condition was no longer suitable for continued chemotherapy, and mozavatan treatment was initiated. Despite the effectiveness of mozavatan treatment, the patient's condition worsened due to rapid tumor progression. The patient died 30 days after completing mozavatan treatment; autopsy revealed direct tumor invasion of the heart and thoracic vertebrae, indicating death from cancer. No other serious adverse events were reported. [2]

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Acute toxicity: Oral LD50 in rats > 1000 mg/kg [1]
-Clinical toxicity: Mozavatan was well tolerated in patients with ectopic ADH syndrome; no serious adverse events (hepatic/nephrotoxicity, electrolyte disturbances) were reported [2]
-Mild gastrointestinal discomfort (nausea, abdominal pain) occurred in 2 of 11 patients, which resolved spontaneously without dose adjustment [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 belongs to the benzamide class of drugs and has a diuretic effect. Based on these research results, mozavatan (Physuline®) was approved as an orphan drug in Japan in 2006 for the treatment of ectopic antidiuretic hormone (ADH) syndrome. It is worth noting that while demeclocycline, lithium chloride, or urea have been reported to be effective for ectopic ADH syndrome, clinical experience indicates that these drugs have limited efficacy. In the United States and the European Union, there are two V2 receptor antagonists on the market—cannivatan (injection) and tolvaptan (oral tablets). Cannivatan is a dual antagonist of both V1a and V2 receptors, and its indication in the United States is "treatment of normovolemic hyponatremia and hypervolemic hyponatremia in hospitalized patients." Tolvaptan, through structural modifications, has a higher affinity for the V2 receptor than its parent drug, mozavaptan. Tolvaptan is indicated in the United States for the treatment of clinically significant hypervolemic and normovolemic hyponatremia, including in patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). In the European Union, it is indicated for the treatment of hyponatremia in adults secondary to SIADH. Mozavaptan is currently the only drug approved in Japan for the treatment of ectopic ADH syndrome, but it has not yet been approved or is under development outside of Japan. In the 43 months since its market launch, 100 patients have received treatment with this drug. According to post-marketing outcomes, the overall clinical efficacy of the drug is similar to that of clinical trials. Mozavaptan has made two important contributions to the treatment of ectopic ADH syndrome. First, short-term use of mozavaptan may enable patients with hyponatremia who would otherwise be unsuitable for platinum-based intensive chemotherapy to receive treatment. Second, mozavaptan may allow patients to be freed from strict fluid intake restrictions, thereby improving their quality of life. Therefore, mozavatan provides a new treatment option for patients with ectopic ADH syndrome, which can be used for both intensive chemotherapy and palliative care. [2]

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Mozavatan (OPC-31260) is a selective oral angiotensin V2 receptor antagonist for the treatment of hyponatremia associated with syndrome of abnormal antidiuretic hormone secretion (SIADH).[1][2]
- Its mechanism of action includes blocking renal V2 receptors, inhibiting AVP-mediated water reabsorption in collecting ducts, and inducing diuresis (water-specific diuresis).[1]
- It effectively corrects hyponatremia by increasing the excretion of free water without altering the sodium or potassium balance.[1][2]
- It has been approved in Japan for the treatment of ectopic ADH syndrome and other types of SIADH.[2]
- Its non-peptide structure and oral bioavailability make it suitable for long-term use in patients with chronic hyponatremia.[1][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)