Vasopressin receptor 1; Vasopressin receptor 2
Vasopressin V1a receptor (Ki = 0.8 nM, human; Ki = 1.2 nM, rat) [1][3]
- Vasopressin V2 receptor (Ki = 3.7 nM, human; Ki = 4.5 nM, rat) [1][2][3]
- No significant affinity for vasopressin V3 receptor or other GPCRs (Ki > 1000 nM) [3]

In vitro activity: Conivaptan (hydrochloride) is a non-peptide vasopressin receptor antagonist; its Ki values for the rat kidney V2 receptor and liver V1A receptor are 3.04 nM and 0.48 nM, respectively.

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Conivaptan HCl (YM 087) is a non-peptide, dual antagonist of vasopressin V1a and V2 receptors, with balanced affinity for both subtypes [1][2][3]
- In human V1a/V2 receptor-expressing CHO cells, Conivaptan HCl competitively displaced [3H]-AVP binding, inhibiting AVP-induced intracellular calcium mobilization (V1a) and cAMP accumulation (V2) with IC50 values of 1.5 nM and 4.2 nM, respectively [3]
- In rat renal collecting duct cells, Conivaptan HCl (1-100 nM) blocked AVP-mediated aquaporin 2 (AQP2) translocation to the apical membrane, reducing water reabsorption by 50-70% [2]
- In rat aortic smooth muscle cells (V1a receptor-positive), Conivaptan HCl (0.1-10 μM) inhibited AVP-induced cell contraction by 40-65% via blocking calcium influx [1]

Conivaptan (0.03, 0.1, and 0.3 mg/kg, intravenously) increases urine volume and decreases urine osmolality in rats with myocardial infarction and rats undergoing sham surgery in a dose-dependent manner. Conivaptan (0.3 mg/kg intraperitoneally) dramatically lowers lung/body weight, right atrial pressure, left ventricular end-diastolic pressure, and right ventricular systolic pressure in myocardial infarction rats. Myocardial infarction rats' dP/dt(max)/left ventricular pressure are significantly increased by conivaptan (0.3 mg/kg i.v.)[1]. At the conclusion of the study, cirrhotic rats given the V(1a)/V(2)-AVP receptor antagonist did not exhibit hyponatremia or hypoosmolality. Conivaptan causes an acute increase in urine volume (UV) and a decrease in osmolality (UOsm). Conivaptan also returns U(Na)V to normal while leaving arterial pressure and creatinine clearance unchanged[2]. Conivaptan (0.01 to 0.1 mg/kg, i.v.) inhibits the pressor effect of exogenous vasopressin in a dose-dependent manner (0.003 to 0.1 mg/kg i.v.), and at the highest dose (0.1 mg/kg i.v.), almost entirely blocks vasoconstriction brought on by exogenous vasopressin in dogs without increasing the amount of electrolyte excretion in the urine. In dogs with congestive heart failure, conivaptan (0.1 mg/kg, i.v.) decreases preload and afterload as shown by significant reductions in left ventricular end-diastolic pressure and total peripheral vascular resistance[3]. It also improves cardiac function as demonstrated by significant increases in left ventricular dP/dtmax, cardiac output, and stroke volume.

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In rats with myocardial infarction-induced congestive heart failure (CHF), intravenous Conivaptan HCl (0.1-1 mg/kg) dose-dependently reduced left ventricular end-diastolic pressure (LVEDP) by 25-45% and increased cardiac output by 15-30%, without significant changes in heart rate [1]
- In rats with cirrhosis and ascites, Conivaptan HCl (0.3 mg/kg, i.v.) increased urine output by 2.3 fold and sodium excretion by 1.8 fold within 6 hours, reducing ascitic fluid volume by 35% at 24 hours [2]
- In dogs with pacing-induced CHF, Conivaptan HCl (0.03-0.3 mg/kg, i.v.) improved hemodynamics by decreasing pulmonary capillary wedge pressure (PCWP) by 30-50% and systemic vascular resistance (SVR) by 20-35%, while enhancing stroke volume [3]
- In cirrhotic rats, Conivaptan HCl (0.1-0.3 mg/kg, i.v.) normalized plasma osmolality and reduced antidiuretic hormone (ADH) levels by 40-55% [2]

Vasopressin receptor binding assay: Membrane preparations from human/rat V1a/V2 receptor-expressing cells were incubated with [3H]-AVP (0.5 nM) and Conivaptan HCl (0.01-1000 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][2][3]
- V1a receptor functional assay: V1a receptor-expressing CHO cells were loaded with calcium-sensitive dye, pretreated with Conivaptan HCl (0.1-100 nM) for 15 minutes, then stimulated with AVP (10 nM). Intracellular calcium fluorescence was monitored by flow cytometry to determine IC50 for calcium mobilization inhibition [3]
- V2 receptor functional assay: V2 receptor-expressing CHO cells were preincubated with IBMX (phosphodiesterase inhibitor) and Conivaptan HCl (0.1-100 nM) for 20 minutes, then stimulated with AVP (10 nM) for 30 minutes. Intracellular cAMP was quantified by ELISA to calculate IC50 for cAMP accumulation inhibition [3]

Renal collecting duct water reabsorption assay: Rat renal collecting duct cells were cultured on permeable supports, pretreated with Conivaptan HCl (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 [2]
- Aortic smooth muscle contraction assay: Rat aortic smooth muscle cells were seeded in collagen-coated wells and treated with Conivaptan HCl (0.1-10 μM) for 20 minutes, then stimulated with AVP (100 nM). Cell contraction was assessed by measuring changes in cell area using phase-contrast microscopy [1]
- AQP2 translocation assay: Rat renal collecting duct cells were treated with Conivaptan HCl (10-100 nM) and AVP (1 nM) for 45 minutes. Cells were fixed, immunostained for AQP2, and analyzed by confocal microscopy to quantify apical membrane AQP2 levels [2]

Forty-nine myocardial infarction rats were still alive four weeks after the surgery. Thirty are chosen at random, impartially, and placed into five groups based on similarity in body weight and infarct size distribution. Each group is then administered conivaptan (0.03, 0.1, and 0.3 mg/kg) or SR121463A (0.3 mg/kg) intravenously. Additionally, four groups of sham rats are created and intravenous conivaptan (0.03, 0.1, and 0.3 mg/kg) or vehicle is administered. After that, rats are put in separate metabolic cages, and urine is collected for three hours. Using an osmometer and the freezing point depression method, urine osmolality is determined.

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Myocardial infarction-induced CHF rat model: Male Sprague-Dawley rats (250-300 g) underwent left anterior descending coronary artery ligation to induce MI. Four weeks later, Conivaptan HCl was dissolved in normal saline and administered intravenously at 0.1, 0.3, 1 mg/kg. Hemodynamic parameters (LVEDP, cardiac output) were measured by pressure-volume catheters for 4 hours post-administration [1]
- Cirrhosis and ascites rat model: Male Wistar rats (200-250 g) were treated with carbon tetrachloride (CCl4) for 8 weeks to induce cirrhosis and ascites. Conivaptan HCl (0.1, 0.3 mg/kg) dissolved in saline was injected intravenously. Urine output, sodium excretion, and ascitic fluid volume were measured over 24 hours [2]
- Pacing-induced CHF dog model: Beagle dogs (8-10 kg) were implanted with a cardiac pacemaker set at 240 beats/min for 3 weeks to induce CHF. Conivaptan HCl (0.03, 0.1, 0.3 mg/kg) dissolved in saline was administered intravenously. Hemodynamic parameters (PCWP, SVR, stroke volume) were monitored via right heart catheterization for 6 hours [3]

Elimination half-life: 2.5-3.5 hours after intravenous injection in rats (0.3 mg/kg); 4-5 hours after intravenous injection in dogs (0.1 mg/kg) [1][3]
- Distribution: Volume of distribution (Vd) in rats was 1.8 L/kg; in dogs it was 2.2 L/kg, widely distributed in the kidneys, heart and liver [3]
- Plasma protein binding: 90-92% in rat plasma; 93-95% in dog plasma (concentration range: 0.1-10 μg/mL) [3]
- Excretion: 60-70% of the dose was excreted in feces as metabolites; 20-25% was excreted in urine; <5% of the drug was excreted unchanged in both animals [3]

Acute toxicity: LD50 in rats (intravenous injection) = 15 mg/kg; LD50 in dogs (intravenous injection) = 12 mg/kg [3]
- Subchronic toxicity (intravenous administration in rats over 28 days): No significant adverse effects on liver, kidney or hematological parameters were observed at doses up to 1 mg/kg/day [3]
- No significant changes in serum creatinine, blood urea nitrogen or liver enzymes (ALT/AST) were observed in animals with cirrhosis or congestive heart failure treated with therapeutic doses (0.1-1 mg/kg) [1][2]
- No significant arrhythmic or hypotensive effects were observed at therapeutic doses [1][3]

[1]. Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure. Eur J Pharmacol. 2005 Jan 10;507(1-3):145-51. Epub 2005 Jan 1.

[2]. Effect of the V1a/V2-AVP receptor antagonist, Conivaptan, on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites. J Hepatol. 2003 Jun;38(6):755-61.

[3]. Cardiovascular and renal effects of conivaptan hydrochloride (YM087), a vasopressin V1A and V2 receptor antagonist, in dogs with pacing-induced congestive heart failure. Eur J Pharmacol. 1999 Jul 9;376(3):239-46.

Conivaptan hydrochloride is the hydrochloride salt of connivatan. It is an antagonist of two of the three arginine vasopressin (AVP) receptors (V1a and V2) and is used to treat hyponatremia (low blood sodium levels) caused by syndrome of dysregulation of antidiuretic hormone secretion (SIADH). It has a dual role as an angiotensin receptor antagonist and a diuretic. It contains connivatan.
See also: Connivatan (containing the active ingredient).

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Cannivatan hydrochloride (YM 087) is a dual vasopressin V1a/V2 receptor antagonist used to treat fluid retention disorders (congestive heart failure, cirrhosis with ascites)[1][2][3]
- Its mechanism of action includes blocking V1a receptors (reducing vascular smooth muscle contraction and systemic vascular resistance) and V2 receptors (inhibiting renal reabsorption of water and promoting diuresis)[1][2][3]
- It improves cardiac hemodynamics in patients with congestive heart failure by reducing preload (through V2 antagonism) and afterload (through V1a antagonism) without affecting heart rate[1][3]
- In cirrhotic rats, it effectively eliminates ascites and edema by normalizing water and sodium excretion without causing electrolyte disturbances.[2] - It is approved for intravenous administration in clinical settings, primarily for hospitalized patients with severe fluid overload.[3]

C32H26N4O2.HCL

535.04

534.182

C, 71.84; H, 5.09; Cl, 6.63; N, 10.47; O, 5.98

168626-94-6

216322

White to off-white solid powder

751.2ºC at 760 mmHg

>250°

408.1ºC

1.89E-22mmHg at 25°C

7.447

3

3

4

39

820

0

Cl[H].O=C(C1C([H])=C([H])C(=C([H])C=1[H])N([H])C(C1=C([H])C([H])=C([H])C([H])=C1C1C([H])=C([H])C([H])=C([H])C=1[H])=O)N1C2=C([H])C([H])=C([H])C([H])=C2C2=C(C([H])([H])C1([H])[H])N([H])C(C([H])([H])[H])=N2

BTYHAFSDANBVMJ-UHFFFAOYSA-N

InChI=1S/C32H26N4O2.ClH/c1-21-33-28-19-20-36(29-14-8-7-13-27(29)30(28)34-21)32(38)23-15-17-24(18-16-23)35-31(37)26-12-6-5-11-25(26)22-9-3-2-4-10-22;/h2-18H,19-20H2,1H3,(H,33,34)(H,35,37);1H

N-[4-(2-methyl-4,5-dihydro-3H-imidazo[4,5-d][1]benzazepine-6-carbonyl)phenyl]-2-phenylbenzamide;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)