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| Targets |
DOV-216,303 targets three monoamine transporters: the serotonin transporter (SERT), the norepinephrine transporter (NET), and the dopamine transporter (DAT). Functional uptake inhibition IC50 values in HEK293 cells expressing human recombinant transporters are: ~14 nM for hSERT, ~20 nM for hNET, and ~78 nM for hDAT. Binding affinity Ki values are reported as 100 nM for SERT, 260 nM for NET, and 210 nM for DAT.
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| ln Vitro |
In vitro radiometric functional uptake studies demonstrated that DOV-216,303 potently inhibits the reuptake of all three monoamines via their corresponding human recombinant transporters expressed in HEK293 cells. The compound exhibits IC50 values of approximately 14 nM for serotonin (5-HT), 20 nM for norepinephrine (NE), and 78 nM for dopamine (DA). This triple reuptake inhibition profile distinguishes DOV-216,303 from both SSRIs (which are selective for SERT) and dual reuptake inhibitors such as venlafaxine and duloxetine. The compound has a molecular weight of 228.12 for the free base and 264.58 for the hydrochloride salt, with a calculated logP of 3.
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| ln Vivo |
In OBX and Sham animals, acute administration of DOV-216,303 (20 mg/kg, i.p.) dramatically raises dopamine, norepinephrine, and serotonin levels [2]. In the medial prefrontal cortex of OBX and Sham mice, chronic administration of DOV 216,303 (20 mg/kg, i.p., for 17 days) raises extracellular concentrations of dopamine, norepinephrine, and serotonin and significantly increases extracellular baseline serum concentration [2].
DOV-216,303 demonstrates antidepressant-like activity in multiple preclinical models predictive of clinical efficacy. In the mouse forced swim test, a standard model for antidepressant screening, DOV-216,303 reduces immobility time. The compound also reverses tetrabenazine-induced ptosis and locomotor depression, indicating its ability to enhance monoaminergic neurotransmission. In the olfactory bulbectomized (OBX) rat model of depression, DOV-216,303 increases extracellular levels of serotonin, norepinephrine, and dopamine in the prefrontal cortex following both acute and chronic administration, although a blunted response was observed following a challenge dose in chronically treated animals. |
| Enzyme Assay |
Functional uptake inhibition assays were performed using HEK293 cells expressing human recombinant transporters. The assay involves measuring the uptake of radiolabeled neurotransmitters ([³H]NE for NET, [³H]5-HT for SERT, and [³H]DA for DAT). Cells are incubated with varying concentrations of DOV-216,303 and the respective radiolabeled substrate. After a designated incubation period, the reaction is terminated, and accumulated radioactivity is measured. IC50 values are determined by fitting the concentration-inhibition data to a sigmoidal curve.
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| Cell Assay |
Cell-based assays for DOV-216,303 utilize HEK293 cells stably expressing human recombinant SERT, NET, or DAT. Cells are cultured under standard conditions and plated in multi-well plates. Varying concentrations of DOV-216,303 are added along with radiolabeled neurotransmitter substrates. After incubation at 37°C, the uptake reaction is stopped by rapid washing, and cells are lysed. The accumulated radioactivity in cell lysates is quantified by liquid scintillation counting to calculate percent inhibition of reuptake.
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| Animal Protocol |
Animal/Disease Models: Male Sprague Dawley rats weighing 290 to 350 grams at the time of OBX or sham surgery [2].
Doses: 20 mg/kg. Management: IP one time/day for 17 days. Experimental Results: Extracellular concentrations of dopamine, norepinephrine, and serotonin were increased in the medial prefrontal cortex of OBX and Sham animals, and extracellular baseline serotonin concentrations were Dramatically increased. Animal/Disease Models: Male Sprague Dawley rats weighing 290 to 350 grams at the time of OBX or sham surgery [2]. Doses: 20 mg/kg. Management: IP once. Experimental Results: Dopamine, norepinephrine, and serotonin levels were Dramatically increased in OBX and Sham animals. Mouse forced swim test: Mice are administered DOV-216,303 (route and dose as specified) prior to being placed in a cylinder of water for 6 minutes. Immobility time is recorded during the last 4 minutes of the test, with reduced immobility time indicating antidepressant-like activity. Tetrabenazine-induced ptosis and locomotor depression model: Mice are pretreated with DOV-216,303 before administration of tetrabenazine (which depletes monoamines). Ptosis (eyelid drooping) is scored, and locomotor activity is measured. Reversal of these tetrabenazine-induced effects indicates enhanced monoaminergic neurotransmission. Olfactory bulbectomized (OBX) rat model: Rats undergo olfactory bulbectomy to induce a depressive-like phenotype. DOV-216,303 is administered acutely or chronically, and microdialysis is performed in the prefrontal cortex to measure extracellular levels of serotonin, norepinephrine, dopamine, and their metabolites. |
| ADME/Pharmacokinetics |
DOV-216,303 is rapidly absorbed following oral administration, with a plasma tmax of 0.7-1.2 hours. The elimination half-life (t1/2) is 3.3-4.4 hours. Both Cmax and AUC values are dose-proportional across the dose range of 5-150 mg. In humans, Cmax values range from 37.4 ng/mL (5 mg single dose) to 712 ng/mL (100 mg single dose) and up to 1,220 ng/mL (150 mg single dose), with doses >10 mg achieving plasma concentrations exceeding the in vitro IC50 values for monoamine reuptake inhibition. The compound shows no remarkable accumulation following 10 days of dosing, with steady-state achieved within a week.
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| Toxicity/Toxicokinetics |
In Phase I clinical studies, DOV-216,303 was safe and well-tolerated in both single-dose (5-150 mg) and multiple-dose (50-100 mg/day for 10 days) evaluations in normal volunteers. At the highest single dose of 150 mg, 4 of 7 subjects reported gastrointestinal disturbances; at a total daily dose of 100 mg in the multiple-dose phase, gastrointestinal disturbances were reported in 4 of 6 volunteers. No significant changes were noted in vital signs, electrocardiogram, hematology, or clinical chemistry at the doses tested. In the Phase II study in depressed patients receiving 100 mg/day DOV-216,303 (50 mg b.i.d.) for two weeks, the side effect profile was not remarkably different from that of the active comparator citalopram (40 mg/day).
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| References |
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| Additional Infomation |
DOV-216,303 (CAS: 86215-36-3; FDA UNII: 06S4712H0T) has the molecular formula C₁₁H₁₁Cl₂N (free base) and C₁₁H₁₂Cl₃N (hydrochloride salt), with a molecular weight of 264.58. The IUPAC name is 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride, and the compound is a racemate containing two defined stereocenters. DOV-216,303 is the prototype “triple” reuptake inhibitor, a mechanistic class hypothesized to produce faster onset and/or greater efficacy than SSRIs or dual reuptake inhibitors due to the inclusion of dopamine potentiation. In August 2004, DOV Pharmaceutical entered a development and commercialization partnership with Merck for the triple reuptake inhibitors (including DOV-216,303 and DOV-21,947) for depression. Phase II clinical data demonstrated that both DOV-216,303 (100 mg/day) and citalopram (40 mg/day) produced significant, time-dependent reductions in HAM-D scores compared to baseline (p < 0.0001), providing preliminary evidence of clinically meaningful antidepressant activity.
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| Molecular Formula |
C11H11NCL2
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| Molecular Weight |
228.11774
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| Exact Mass |
227.027
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| Elemental Analysis |
C, 57.92; H, 4.86; Cl, 31.08; N, 6.14
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| CAS # |
66504-40-3
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| Related CAS # |
Amitifadine hydrochloride;410074-74-7;DOV-216,303;86215-36-3
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| PubChem CID |
9795276
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| Appearance |
Colorless to light yellow ointment
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| LogP |
3.183
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
1
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
14
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| Complexity |
245
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=C(C=C1C23CC3CNC2)Cl)Cl
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| InChi Key |
BSMNRYCSBFHEMQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H11Cl2N/c12-9-2-1-7(3-10(9)13)11-4-8(11)5-14-6-11/h1-3,8,14H,4-6H2
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| Chemical Name |
1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
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| Synonyms |
DOV-216,303; DOV216,303; DOV216303; DOV-216303; DOV 216303; 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane; 66504-40-3; MFCD22381599; 1-(3,4-Dichloro-phenyl)-3-aza-bicyclo[3.1.0]hexane; CHEMBL528995;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
DMSO : ≥ 125 mg/mL (~547.96 mM)
Ethanol : ~100 mg/mL (~438.37 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (9.12 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 20.8 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: ≥ 2.08 mg/mL (9.12 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.3837 mL | 21.9183 mL | 43.8366 mL | |
| 5 mM | 0.8767 mL | 4.3837 mL | 8.7673 mL | |
| 10 mM | 0.4384 mL | 2.1918 mL | 4.3837 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.
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