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| Targets |
SUVN-G3031 targets the histamine H3 receptor (H3R), a presynaptic G protein-coupled receptor that regulates the release of histamine and other neurotransmitters in the central nervous system. It is a potent and selective H3R inverse agonist. It has a Ki of 8.73 nM for human H3R (hH3R) and 9.8 nM for rat H3R (rH3R), indicating no interspecies differences.
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| ln Vitro |
Samelisant has very high selectivity for H3R and inverse agonist action. Following administration of 1, 10, and 100 nM Samelisant, the histamine pEC50 value (8.5) of the human H3 receptor increased to 8.2, 7.3, and 6.2, respectively. Rat H3 receptors' histamine pEC50 value (8.2) rose to 7.9, 7.4, and 6.4 following treatment with 1, 10, and 100 nmol/L Samelisant, respectively [1]. Samelisant exhibits reversible binding to the positive site; Kb values of 1.3 nM and 1.1 nM, respectively, are inferred from the pA2 values of human and rat H3R [1]. Samelisant has no effect on dopamine levels in the striatum or nucleus accumbens, but it does modify dopamine and norepinephrine levels in the cerebral cortex [1].
SUVN-G3031 is a potent and selective histamine H3 receptor inverse agonist with a Ki of 8.73 nM for human H3R. It exhibited an IC50 of 20 nM in a [³⁵S]-GTPγS binding assay using CHO-K1 cells expressing human H3R membranes, showing progressive inhibition of (R)-α-methylhistamine-induced agonist activity. |
| ln Vivo |
Samelisant (10 and 30 mg/kg, orally administered) dramatically increased wakefulness while decreasing non-rapid eye movement (NREM) sleep in orexin deficient mice undergoing sleep electroencephalography (EEG) [1]. Moreover, samelisant dramatically delays the beginning of direct rapid eye movement (REM) sleep episodes (DREM), proving its anticonvulsant properties in narcolepsy-related animal models [1]. When mice are given Samelisant, their levels of farmethylhistamine rise in a dose-dependent manner, suggesting that histaminergic neurotransmission has been activated [1].
SUVN-G3031 is orally active and brain penetrant. In vivo studies have demonstrated its potential for the treatment of cognitive disorders, dementia, ADHD, epilepsy, sleep disorders, obesity, schizophrenia, eating disorders, and pain. Specific animal model data and dosing regimens are not extensively detailed. |
| Enzyme Assay |
The binding affinity of SUVN-G3031 to the histamine H3 receptor is assessed using radioligand binding assays with membrane preparations from cells expressing recombinant human or rat H3 receptors. Competition binding experiments are performed with increasing concentrations of SUVN-G3031 against a fixed concentration of a radiolabeled H3 receptor ligand (e.g., [³H]Nα-methylhistamine). Non-specific binding is determined in the presence of an excess of a reference H3 receptor ligand. Ki values are calculated from competition curves.
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| Cell Assay |
The functional activity of SUVN-G3031 at the H3 receptor is evaluated using [³⁵S]-GTPγS binding assays with membranes from CHO-K1 cells expressing human H3R. Increasing concentrations of SUVN-G3031 are incubated with membranes, GDP, and [³⁵S]-GTPγS. The amount of [³⁵S]-GTPγS bound to membranes is measured by scintillation counting. Inverse agonist activity is indicated by inhibition of basal [³⁵S]-GTPγS binding. Antagonist activity is assessed by inhibition of agonist (e.g., (R)-α-methylhistamine)-stimulated binding.
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| Animal Protocol |
Animal/Disease Models: Male Wistar rat or male C57BL6J mouse [1]
Doses: 1, 3, 10 and 30 mg/kg Route of Administration: Oral Experimental Results: Dose producing t-MH levels in frontal cortex, hypothalamus and hypothalamus Dependently increases cerebrospinal fluid (CSF) in male Wistar rats. Dramatically increased t-MH levels in the frontal cortex, striatum and hypothalamus of mice. SUVN-G3031 is administered orally to animal models of various CNS disorders. In rodent models, the compound is given at various doses via oral gavage. Efficacy is assessed using appropriate behavioral tests depending on the indication: cognitive tests (e.g., Morris water maze, novel object recognition) for cognitive disorders, activity monitors for ADHD, seizure models for epilepsy, sleep recordings for sleep disorders, and food intake measurements for obesity. |
| ADME/Pharmacokinetics |
SUVN-G3031 is orally bioavailable and BBB permeable. It has a Ki of 8.73 nM for human H3R and 9.8 nM for rat H3R. The compound is a hydrochloride salt with a molecular weight of 446.41. Specific pharmacokinetic parameters such as half-life and bioavailability are not extensively detailed.
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| Toxicity/Toxicokinetics |
The toxicity profile of SUVN-G3031 is not extensively documented in standard reference sources. As a histamine H3 receptor inverse agonist, potential adverse effects may include those related to enhanced histaminergic neurotransmission, such as insomnia, anxiety, or gastrointestinal effects. Specific LD50 values and organ-specific toxicity data are not readily available.
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| References | |
| Additional Infomation |
SUVN-G3031 HCl (CAS# 1394808-20-8) is also known as Samelisant dihydrochloride and SUVN-G3031. It is a potent, selective, orally active histamine H3 receptor (H3R) inverse agonist. The compound has potential for the treatment of cognitive impairment, dementia, ADHD, epilepsy, sleep disorders, obesity, schizophrenia, eating disorders, and pain. It is a research compound developed by Suven Pharmaceuticals.
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| Molecular Formula |
C21H33CL2N3O3
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| Molecular Weight |
446.411023855209
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| Exact Mass |
445.189
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| Elemental Analysis |
C, 56.50; H, 7.45; Cl, 15.88; N, 9.41; O, 10.75
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| CAS # |
1394808-20-8
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| Related CAS # |
Samelisant free base;1394808-82-2
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| PubChem CID |
60151476
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| Appearance |
Off-white to light yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
463
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.Cl.O(C1C=CC(=CC=1)NC(CN1CCOCC1)=O)C1CCN(CC1)C1CCC1
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| InChi Key |
LCPQCTBHZPMVFX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H31N3O3.2ClH/c25-21(16-23-12-14-26-15-13-23)22-17-4-6-19(7-5-17)27-20-8-10-24(11-9-20)18-2-1-3-18;;/h4-7,18,20H,1-3,8-16H2,(H,22,25);2*1H
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| Chemical Name |
N-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-2-morpholin-4-ylacetamide;dihydrochloride
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| Synonyms |
SUVN-G3031; SUVN G3031; SUVN-G 3031.
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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 : ~62.5 mg/mL (~140.01 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.66 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 (4.66 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 20.8 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: ≥ 2.08 mg/mL (4.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2401 mL | 11.2005 mL | 22.4009 mL | |
| 5 mM | 0.4480 mL | 2.2401 mL | 4.4802 mL | |
| 10 mM | 0.2240 mL | 1.1200 mL | 2.2401 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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