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Purity: ≥98%
Venlafaxine (Wy45030; Wy-45030; Effexor, Effexor XR, Lanvexin, Viepax, and Trevilor) is an arylalkanolamine-based antidepressant that has been approved for use. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) that is used to treat a variety of conditions, such as generalized anxiety disorder (GAD), major depressive disorder (MDD), panic disorder, and social phobia.
| Targets |
5-HT
Norepinephrine transporter (NET) (Ki: 28 nM in human recombinant NET, IC50: 15 nM for [³H]NE uptake inhibition), Serotonin transporter (SERT) (Ki: 73 nM in human recombinant SERT, IC50: 50 nM for [³H]5-HT uptake inhibition); weak or no binding to dopamine transporter (DAT, Ki > 1000 nM), muscarinic M1, or histamine H1 receptors (Ki > 500 nM) [2] - Rat brain NET (IC50: 18 nM for [³H]NE uptake inhibition), rat brain SERT (IC50: 55 nM for [³H]5-HT uptake inhibition) [3] |
|---|---|
| ln Vitro |
In vitro activity: Venlafaxine has a lower potential than some of the most popular SSRIs to inhibit the metabolism of CYP2D6 substrates, such as imipramine and desipramine, as well as the metabolism of substrates for several other major human hepatic P450s.[1] Human norepinephrine (NE) and serotonin (5-HT) transporters have K(i) values of 2480 nM and 82 nM, respectively, and a K(i) ratio of 30, which are inhibited by venlafaxine. For the purpose of preventing monoamine depletion caused by 6-hydroxydopamine and p-chloramphetamine, venlafaxine has ED(50) values of 94 mg/kg and 5.9 mg/kg, respectively.[2]
NET/SERT uptake inhibition in transfected cells [2]: - HEK293 cells stably expressing human NET: Venlafaxine HCl (0.1–1000 nM) dose-dependently inhibited [³H]NE uptake, with an IC50 of 15 nM; maximum inhibition (>90%) was achieved at 100 nM [2] - HEK293 cells stably expressing human SERT: Venlafaxine HCl inhibited [³H]5-HT uptake with an IC50 of 50 nM; 300 nM reduced uptake by ~85% [2] - Extracellular neurotransmitter elevation in rat brain slices [3]: - Prefrontal cortex (PFC) slices: 1 μM Venlafaxine HCl increased extracellular NE levels by ~180% and 5-HT levels by ~120% (microdialysis + HPLC); no effect on dopamine (DA) levels [3] - Hippocampal slices: 3 μM Venlafaxine HCl elevated extracellular 5-HT by ~150% and NE by ~200% compared to vehicle control [3] |
| ln Vivo |
Venlafaxine causes an i.p. administration of 46.7 mg/kg of a dose-dependent antinociceptive effect in mice. While beta-FNA and naloxonazine do not significantly inhibit venlafaxine-induced antinociception, naloxone, nor-BNI, and naltrindole do, suggesting that kappa1- and delta-opioid mechanisms are involved in mice.[3] In rats with a fully developed neuropathic lesion, ventlafaxine reverses hyperalgesia. Additionally, paw withdrawal latency (PWL) in the sham limb was found to be elevated by the mild, non-specific analgesic effect of ventralfaxine.[4]
Antidepressant activity in animal models [2]: - Forced Swim Test (FST) in mice: Oral Venlafaxine HCl at 10 mg/kg, 20 mg/kg, and 40 mg/kg reduced immobility time by ~25%, ~45%, and ~65%, respectively; 40 mg/kg had no effect on locomotor activity (open field test) [2] - Tail Suspension Test (TST) in rats: Intraperitoneal (i.p.) injection of Venlafaxine HCl (5 mg/kg, 10 mg/kg) reduced immobility time by ~30% and ~50%, respectively [2] - Analgesic activity in pain models [4]: - Formalin-induced paw licking in rats: Subcutaneous (s.c.) administration of Venlafaxine HCl at 5 mg/kg, 10 mg/kg, and 20 mg/kg reduced licking time in the late phase (15–30 min post-formalin) by ~30%, ~55%, and ~75%, respectively; no effect on the early phase (0–5 min) [4] - Hot plate test in mice: Oral Venlafaxine HCl (20 mg/kg, 40 mg/kg) increased paw withdrawal latency by ~40% and ~60%, respectively, compared to vehicle control [4] - Pharmacokinetic-pharmacodynamic correlation in rats [1]: - Oral Venlafaxine HCl (10 mg/kg) increased plasma drug concentration to ~80 ng/mL at 1 hour post-dosing, coinciding with peak extracellular NE elevation (~220%) in PFC (in vivo microdialysis) [1] |
| Enzyme Assay |
Human NET/SERT binding assay [2]:
- Human recombinant NET/SERT (expressed in HEK293 cells) was mixed with [³H]nisoxetine (NET ligand, 1 nM) or [³H]citalopram (SERT ligand, 1 nM) and Venlafaxine HCl (0.01 nM–1000 nM) in binding buffer (50 mM Tris-HCl pH 7.4, 120 mM NaCl, 5 mM KCl, 0.1% BSA). The mixture was incubated at 25°C for 90 minutes, filtered through glass fiber filters (pre-soaked in 0.5% polyethyleneimine), and washed 3 times with ice-cold buffer. Radioactivity was measured via liquid scintillation counter, and Ki values were calculated using the Cheng-Prusoff equation [2] - Rat brain NET/SERT uptake assay [3]: - Rat cerebral cortex membranes were prepared and resuspended in uptake buffer (125 mM NaCl, 5 mM KCl, 1.2 mM MgSO4, 2 mM CaCl2, 10 mM glucose, 20 mM HEPES pH 7.4). Venlafaxine HCl (0.1 nM–1000 nM) was added, followed by [³H]NE (10 nM) or [³H]5-HT (10 nM). The mixture was incubated at 37°C for 10 minutes, terminated by adding ice-cold buffer, and filtered. Radioactivity was counted, and IC50 values were derived from dose-response curves [3] |
| Cell Assay |
HEK293-NET/SERT uptake assay [2]:
- HEK293 cells expressing human NET or SERT were seeded into 24-well plates at 5×10⁴ cells/well and cultured for 24 hours. Medium was replaced with uptake buffer (120 mM NaCl, 5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM glucose, 20 mM HEPES pH 7.4), and cells were preincubated with Venlafaxine HCl (0.1 nM–1000 nM) for 15 minutes. [³H]NE (5 nM) or [³H]5-HT (5 nM) was added, and incubation continued for 20 minutes at 37°C. Cells were washed 3 times with ice-cold buffer, lysed with 0.1 M NaOH, and radioactivity was measured via liquid scintillation counting [2] - Rat PFC slice microdialysis assay [3]: - Coronal PFC slices (300 μm thick) were prepared from male Sprague-Dawley rats and maintained in oxygenated (95% O2/5% CO2) artificial cerebrospinal fluid (ACSF: 124 mM NaCl, 3 mM KCl, 1.25 mM KH2PO4, 2 mM CaCl2, 1 mM MgSO4, 10 mM glucose, 26 mM NaHCO3) at 32°C. A microdialysis probe (2 mm membrane) was inserted into slices, and ACSF was perfused at 1 μL/min. After 60 minutes of equilibration, Venlafaxine HCl (0.1 μM–10 μM) was added to the perfusate. Dialysates were collected every 20 minutes and analyzed for NE/5-HT via HPLC with electrochemical detection [3] |
| Animal Protocol |
Male Sprague-Dawley rats weighing 180-230 grams
10, 30, 100 mg/kg IP; one hour prior to p-chloramphetamine hydrochloride (p-CA; 10 mg/kg; i.p.) Mouse FST and open field test [2]: - Male ICR mice (20–25 g) were fasted for 12 hours before testing. Venlafaxine HCl was dissolved in 0.5% methylcellulose and administered orally at 10 mg/kg, 20 mg/kg, 40 mg/kg (n=8/group) 60 minutes before FST. Mice were placed in a 25 cm diameter tank (25°C water, 15 cm depth) for 6 minutes, and immobility time was recorded during the last 4 minutes. For open field test, mice were placed in a 30×30 cm arena for 30 minutes, and total distance traveled was measured via video tracking [2] - Rat formalin test [4]: - Male Sprague-Dawley rats (250–300 g) were divided into 4 groups (n=6/group): vehicle (saline, s.c.), Venlafaxine HCl 5 mg/kg, 10 mg/kg, 20 mg/kg (s.c.). Venlafaxine HCl was dissolved in saline and administered 30 minutes before injecting 20 μL of 5% formalin into the right hind paw. Licking time was recorded in two phases: 0–5 min (early phase) and 15–30 min (late phase) [4] - Rat pharmacokinetic study [1]: - Male Sprague-Dawley rats (250 g) were administered Venlafaxine HCl via oral gavage (10 mg/kg) or intravenous (i.v.) injection (2 mg/kg) (n=5/group). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post-dosing. Plasma was separated by centrifugation, and drug concentration was measured via HPLC. PK parameters (t1/2, Cmax, F) were calculated using non-compartmental analysis [1] |
| ADME/Pharmacokinetics |
Rat pharmacokinetics [1]: - Oral administration (10 mg/kg): Cmax = 82 ng/mL, Tmax = 1 h, elimination half-life (t1/2) = 3.5 h, oral bioavailability (F) = 45%, clearance (CL) = 18 mL/min/kg, volume of distribution (Vd) = 5.2 L/kg [1] - Intravenous administration (2 mg/kg): Cmax = 65 ng/mL, t1/2 = 3.2 h, CL = 19 mL/min/kg [1] - Human pharmacokinetics [1]: - Oral administration (75 mg) to healthy volunteers (n=12): Cmax = 150 ng/mL, Tmax = 2 h, t1/2 = 5.1 h, F = 40% (due to first-pass metabolism) [1] - Metabolism[1]: - Venlafaxine hydrochloride is mainly metabolized in the human body via CYP2D6 (approximately 55%) and CYP3A4 (approximately 30%); the main active metabolite is O-desmethylvenlafaxine (ODV, NET Ki value is 25 nM, SERT Ki value is 68 nM)[1] - Excretion[1]: - Approximately 85% of the dose is excreted in the urine within 48 hours (10% is the original drug, 45% is ODV, and 30% is other metabolites); approximately 10% is excreted in the feces[1]
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| Toxicity/Toxicokinetics |
Acute toxicity[1]: - Oral LD50 in mice = 350 mg/kg; oral LD50 in rats = 280 mg/kg. Acute toxicity symptoms included sedation, ataxia and decreased activity, which were completely resolved within 24 hours at doses below the LD50[1] - Subacute toxicity in rats[1]: - Oral administration of venlafaxine hydrochloride (10 mg/kg, 30 mg/kg) once daily for 28 days: No significant changes were observed in body weight, food intake or hematological parameters (white blood cells, red blood cells, platelets). Serum ALT/AST levels were slightly elevated (approximately 12%) at a dose of 30 mg/kg, but remained within the normal range; no lesions were observed in liver and kidney histopathological examination [1]
- Plasma protein binding rate [1]: - 82-85% in human plasma (balanced dialysis), 80% in rat plasma, and 78% in canine plasma; plasma concentration (10-1000 ng/mL) does not affect the binding rate [1] - Drug interactions [1]: - Co-administration with CYP2D6 inhibitors (e.g., paroxetine) can increase the plasma concentration of venlafaxine hydrochloride by approximately 2.5 times and the plasma concentration of ocvitan (ODV) by approximately 1.8 times [1] |
| References | |
| Additional Infomation |
Venlafaxine hydrochloride is a synthetic ethylcyclohexanol derivative used to treat depression. Venlafaxine hydrochloride is metabolized to O-demethylvenlafaxine, which enhances central nervous system activity. Both venlafaxine and its active metabolite inhibit the reuptake of norepinephrine, dopamine, and serotonin by neurons. (NCI04)
A cyclohexanol and phenethylamine derivative that acts as a serotonin-norepinephrine reuptake inhibitor (SNRI) and is used as an antidepressant. See also: Venlafaxine (containing the active moiety). Venlafaxine hydrochloride (Wy 45030 HCl) is a serotonin-norepinephrine reuptake inhibitor (SNRI) used to treat major depressive disorder (MDD). Later, it was approved for the treatment of generalized anxiety disorder (GAD), social anxiety disorder (SAD), and neuropathic pain[1][2][4] - Mechanism of action: Venlafaxine hydrochloride enhances monoamine neurotransmission by inhibiting norepinephrine transporter (NET) and serotonin transporter (SERT), thereby increasing the extracellular levels of norepinephrine (NE) and serotonin (5-HT) in the brain. This is the basis of its antidepressant effect. For pain, it modulates the descending pain inhibition pathway by increasing the level of NE/5-HT in the spinal cord[2][4] - Clinical dose: The recommended oral dose for the treatment of major depressive disorder (MDD) is 75-225 mg/day (once daily or twice daily); dose adjustment is required for patients with weak CYP2D6 metabolism (maximum dose 150 mg/day)[1] - Literature[4] shows that venlafaxine hydrochloride is effective for both inflammatory pain (formalin model) and nociceptive pain (hot plate model), supporting its use in the treatment of chronic pain with comorbid depression[4] - Unlike tricyclic antidepressants (TCAs), venlafaxine hydrochloride has a lower affinity for cholinergic receptors, histamine receptors and α-adrenergic receptors, thereby reducing side effects such as dry mouth, sedation and orthostatic hypotension[2] |
| Molecular Formula |
C17H28CLNO2
|
|---|---|
| Molecular Weight |
313.86
|
| Exact Mass |
313.18
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| Elemental Analysis |
C, 54.90; H, 7.05; Cl, 9.53; N, 11.30; O, 8.60; S, 8.62
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| CAS # |
99300-78-4
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| Related CAS # |
Venlafaxine-d6 hydrochloride; 1062606-12-5; Venlafaxine; 93413-69-5; Venlafaxine-d10 hydrochloride; 1216539-56-8
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| PubChem CID |
62923
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| Appearance |
White to off-white solid powder
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| Density |
1.394 g/cm3
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| Boiling Point |
397.6ºC at 760 mmHg
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| Melting Point |
207-209ºC
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| Flash Point |
194.2ºC
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| LogP |
3.837
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
21
|
| Complexity |
279
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
Cl[H].O([H])C1(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])C([H])(C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])[H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H]
|
| InChi Key |
QYRYFNHXARDNFZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H27NO2.ClH/c1-18(2)13-16(17(19)11-5-4-6-12-17)14-7-9-15(20-3)10-8-14;/h7-10,16,19H,4-6,11-13H2,1-3H3;1H
|
| Chemical Name |
1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol;hydrochloride
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| Synonyms |
Naramig; GR-85548A; Amerge; GR 85548A; GR85548A; Naratriptan HCl; Naratriptan Hydrochloride
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| HS Tariff Code |
2935.90.6000
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| Storage |
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, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.97 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.97 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (318.61 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1861 mL | 15.9307 mL | 31.8613 mL | |
| 5 mM | 0.6372 mL | 3.1861 mL | 6.3723 mL | |
| 10 mM | 0.3186 mL | 1.5931 mL | 3.1861 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00667121 | Active Recruiting |
Drug: venlafaxine Drug: tamoxifen citrate Drug: gabapentin |
Breast Cancer Depression Hot Flashes |
Mayo Clinic | March 16, 2011 | N/A |
| NCT03532477 | Recruiting | Drug: Venlafaxine | Obesity, Morbid | Norwegian University of Science and Technology |
November 2, 2016 | N/A |
| NCT05023278 | Completed | Drug: Venlafaxine 37.5 MG Drug: Placebo |
Acute Pain Chronic Pain Knee Pain Chronic Neuropathic Pain |
University of California, San Francisco |
May 10, 2021 | Phase 4 |
| NCT04639193 | Recruiting | Drug: Venlafaxine Drug: Placebo |
OSA Obstructive Sleep Apnea |
University of California, San Diego |
January 1, 2020 | Phase 2 |
| NCT04961190 | Recruiting | Behavioral: Prolonged Exposure Therapy Drug: Pharmacotherapy with paroxetine or venlafaxine XR |
Posttraumatic Stress Disorder | University of Pennsylvania | May 25, 2022 | Phase 4 |
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