| Size | Price | |
|---|---|---|
| 25mg | ||
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
TAAR; 5-HT1A Receptor
TAAR1 (trace amine-associated receptor 1), 5-HT1A (serotonin 5-HT1A receptor) |
|---|---|
| ln Vitro |
SEP-363856 (10 μM) has a >50% specific binding inhibition of D2, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptor[1].
SEP-363856 S-isomer activates TAAR1 and 5-HT1A receptors with high potency. It demonstrates G-protein recruitment and GIRK channel activation at TAAR1, with pEC50 values of approximately 6.08 for Gα recruitment. The S-isomer shows antipsychotic-like activity in preclinical models without significant D2 receptor occupancy, distinguishing it from typical antipsychotics. |
| ln Vivo |
SEP-363856 displays behavioral traits resembling those of well-known antipsychotics and possesses CNS activity at concentrations of 0.3, 1 and 10 mg/kg, i.p. [1]. The oral dosage of SEP-363856 (0.3, 1 and 10 mg/kg) is effective in reducing PCP-induced hyperactivity [1]. REM sleep is reduced, REM sleep latency is increased, and cumulative wake time (W) is increased when SEP-363856 (1, 3 and 10 mg/kg) is administered orally [1].
In vivo, SEP-363856 S-isomer demonstrates antipsychotic-like efficacy in rodent models including inhibition of phencyclidine-induced hyperlocomotion and prepulse inhibition deficits. It produces dose-dependent effects on dopamine and serotonin turnover in brain regions. At doses of 1-30 mg/kg, it is well tolerated and produces sustained receptor engagement. |
| Enzyme Assay |
n Vitro and In Vivo 5-HT1A and D2 Receptor Occupancy Studies.[1] In vitro autoradiography was used to determine the effects of SEP-856 on [3H]-8-OH-DPAT binding to 5-HT1A receptors in rat brain sections. In vivo occupancy of SEP-856 at D2 receptors was measured with [3H]-raclopride in Sprague-Dawley rats and with [18F]-fallypride–positron emission tomography in nonhuman primates. For details, refer to Supplemental Material.[1]
TAAR1 and 5-HT1A receptor binding was assessed using membrane preparations from cells expressing recombinant receptors and radiolabeled ligands. Serial dilutions of SEP-363856 S-isomer were incubated with membranes and radioligand. IC50 values were determined by nonlinear regression analysis. Functional activity was assessed by GTPγS binding and cAMP assays. |
| Cell Assay |
Patch–Clamp Recordings in the Dorsal Raphe Nucleus and Ventral Tegmental Area.[1] In vitro whole–cell patch–clamp recording techniques were used in isolated slice preparations (male C57BL/6J mice, 4–16 weeks) of the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) to investigate the effects of SEP-856 on neuronal activity. The experiments examined the effects of SEP-856 (1–30 μM) on the activity of DRN and VTA neurons that were characterized by their electrophysiological properties and/or their sensitivity to application of the 5-HT1A receptor agonist 8-OH-DPAT (DPAT; 10 μM). Subsequently, effects mediated via the TAAR1 and/or via the 5-HT1A receptor were investigated using the selective antagonist N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB; 0.05–1 μM) and the selective antagonist WAY-100635 (WAY-635; 10 μM), respectively. All compounds were dissolved in either DMSO or ddH2O and diluted with artificial cerebrospinal fluid (aCSF) to a final concentration from a minimum 1000-fold higher stock concentration (maximum slice DMSO concentration 0.1%). Whole–cell patch–clamp recordings were performed at room temperature using the blind version of the patch–clamp technique with either Axopatch 1D or Multiclamp 700B amplifiers. For detailed methods, refer to the Supplemental Material.[1]
Cells expressing TAAR1 or 5-HT1A (e.g., CHO-K1 or HEK293) were cultured and treated with serial dilutions of SEP-363856 S-isomer. G-protein recruitment was measured by HTRF-based assays. GIRK channel activation was assessed by patch-clamp electrophysiology. cAMP accumulation was measured by luminescence-based assays. |
| Animal Protocol |
Animal/Disease Models: Acute treatment with phencyclidine (PCP) can induce intense hyperactivity in rodents [1].
Doses: 0.3, 1 and 3 mg/kg. Doses: Take once orally. Experimental Results: Dose-dependent inhibition of PCP-induced hyperkinetic responses in C57Bl/6J mice (one-way ANOVA F (5, 59) = 18.96, p < 0.0001; Tukey's post hoc test, p < 0.05) 50% effective dose (ED50) is approximately 0.3 mg/kg. Animal/Disease Models: Male Sprague Dawley rat[1]. Doses: 1, 2 and 5 mg/kg. Mode of Route of Administration: intravenous (iv) (iv)injection. (pharmacokinetic/PK/PK analysis). Experimental Results: Maximum plasma concentrations were reached within 0.5 hrs (hrs (hours)) in mice and rats and within 6 ± 2.83 hrs (hrs (hours)) in monkeys. After oral administration (10 mg/kg), it penetrates the mouse and rat brains with mean brain to plasma AUC ratios of approximately 3, respectively. Rodents (mice or rats) were administered SEP-363856 S-isomer by oral gavage at doses of 1-30 mg/kg. Antipsychotic-like activity was assessed in phencyclidine-induced hyperlocomotion and prepulse inhibition models. Brain tissues were collected for analysis of dopamine and serotonin metabolite levels by HPLC. Receptor occupancy was assessed by ex vivo binding assays. |
| References |
[1]. Dedic N, et al. SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action. J Pharmacol Exp Ther. 2019 Oct;371(1):1-14.
|
| Additional Infomation |
Ulotaront belongs to the thienopyran class of compounds with the molecular formula 4,7-dihydro-5H-thieno[2,3-c]pyran, with a (methylamino)methyl group substituted at the 7S position. It is a trace amine-associated receptor 1 (TAR1) and serotonin 1A (5-HT1A) receptor agonist and has been shown to be effective in patients with schizophrenia. It possesses various pharmacological activities, including as a TAR1 agonist, psychotropic drug, antidepressant, antipsychotic, and serotonergic agonist. It is a secondary amine compound belonging to the thienopyran class. SEP-363856 is a novel psychotropic drug currently under investigation for its efficacy in treating schizophrenia. Unlike other drugs used to treat this disease, SEP-363856 does not bind to dopamine D2 receptors but instead acts on trace amine-associated receptor 1 (TAAR1) and serotonin 1A receptors (5-HT1A). SEP-363856 was developed by Sunovion Pharmaceuticals. Preliminary clinical studies suggest that this drug may be effective for both positive and negative symptoms of schizophrenia. Negative symptoms of schizophrenia are more difficult to treat and may include emotional blunting, anhedonia, and social withdrawal. Further clinical trials of SEP-363856 are needed to confirm its safety and efficacy.
|
| Molecular Formula |
C9H13NOS
|
|---|---|
| Molecular Weight |
183.2706
|
| Exact Mass |
183.071
|
| CAS # |
1310426-33-5
|
| Related CAS # |
SEP-363856 hydrochloride;1310422-41-3;(Rac)-SEP-363856;1310426-29-9
|
| PubChem CID |
89532783
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
0.9
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
12
|
| Complexity |
154
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CNC[C@H]1C2=C(CCO1)C=CS2
|
| InChi Key |
ABDDQTDRAHXHOC-QMMMGPOBSA-N
|
| InChi Code |
InChI=1S/C9H13NOS/c1-10-6-8-9-7(2-4-11-8)3-5-12-9/h3,5,8,10H,2,4,6H2,1H3/t8-/m0/s1
|
| Chemical Name |
1-[(7S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]-N-methylmethanamine
|
| Synonyms |
SEP363856; SEP 363856; Ulotaront; SEP-856; 1310426-33-5; UNII-3K6270MG59; 3K6270MG59; 1-[(7S)-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]-N-methylmethanamine; SEP363856;
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.4564 mL | 27.2822 mL | 54.5643 mL | |
| 5 mM | 1.0913 mL | 5.4564 mL | 10.9129 mL | |
| 10 mM | 0.5456 mL | 2.7282 mL | 5.4564 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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