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| Targets |
Histamine H3 receptor (H3R). Cipralisant enantiomer is a potent and selective antagonist/inverse agonist of the H3 receptor. The rat Ki is 0.47 nM. By blocking the presynaptic H3 autoreceptor and heteroreceptor, it increases the release of histamine, acetylcholine, dopamine, and norepinephrine in the brain, which can enhance wakefulness, attention, memory, and reduce appetite.
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| ln Vitro |
In vitro, Cipralisant enantiomer binds to the H3 receptor with extremely high affinity (rat Ki = 0.47 nM). It is a potent inverse agonist, as measured by [3⁵S]GTPgammaS binding assays, decreasing basal G protein activation. In cell lines expressing H3R, the compound increases forskolin‑stimulated cAMP accumulation (by blocking constitutive Gi activity). The enantiomer is the active component of the racemate; the other enantiomer is less potent.
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| ln Vivo |
In vivo, Cipralisant (the racemate or the enantiomer) has been studied in animal models of cognitive impairment, narcolepsy, and obesity. It increases wakefulness, reduces slow‑wave sleep, and enhances theta band activity in the EEG. It also reduces food intake in rodent models by increasing hypothalamic histamine levels. The compound has shown procognitive effects in the novel object recognition test and the Morris water maze. It is orally active.
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| Enzyme Assay |
Standard cell‑free H3 receptor binding assays use membranes from rat cerebral cortex (cortex, where H3 receptors are abundant) or from CHO/HEK‑293 cells expressing the human H3 receptor. Membranes (20‑30 ug protein) are incubated with 0.5‑1 nM [3H]N‑alpha‑methylhistamine ([3H]NAMH, selective H3 agonist) and varying concentrations of Cipralisant enantiomer (0.001‑1000 nM) in 50 mM Tris‑HCl buffer (pH 7.4) containing 5 mM MgCl2, 1 mM EGTA, and 0.1% BSA for 60‑90 min at 23degC. Non‑specific binding is determined with 10 uM imetit or 10 uM unlabeled NAMH. Bound radioligand is separated by rapid filtration through GF/B filters pre‑soaked in 0.3% PEI, washed, and counted. The Ki is 0.47 nM. For functional assays, [3⁵S]GTPgammaS binding is performed: membranes are incubated with GDP (10 uM), [3⁵S]GTPgammaS (0.1 nM), and varying concentrations of the compound (0.001‑1000 nM). A decrease in basal binding indicates inverse agonism.
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| Cell Assay |
For cellular cAMP accumulation assays, CHO cells expressing the human H3 receptor are seeded in 96‑well plates (40,000 cells/well) in DMEM/10% FBS for 48 h. Cells are pre‑incubated with 0.5 mM IBMX for 15 min, then treated with Cipralisant enantiomer (0.001‑1000 nM) in the presence of 1 uM forskolin. After 30 min, cAMP levels are quantified by HTRF or ELISA. An increase in cAMP (vs. vehicle control) is measured (blockade of constitutive Gi activity). The EC50 is in the low nM range. For calcium mobilization assays (not typical for H3, but can be done with a chimeric G‑protein), cells are loaded with Fluo‑4 AM and stimulated with the compound.
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| Animal Protocol |
In vivo studies are performed in male C57BL/6 mice (20‑30 g) or Sprague‑Dawley rats (200‑300 g). Cipralisant enantiomer is formulated in 0.5% methylcellulose or 10% DMSO/40% PEG300/5% Tween‑80/45% saline and administered orally (0.03‑3 mg/kg) 30‑60 min before testing. For wakefulness studies (EEG/EMG): mice are implanted with EEG/EMG electrodes. At the beginning of the light cycle (inactive period), the compound is administered, and recordings are made for 6‑8 hours. Cipralisant enantiomer increases wakefulness and decreases non‑REM and REM sleep. For the novel object recognition (NOR) test: mice are treated with the compound (0.1‑1 mg/kg PO) 30 min before acquisition (two identical objects). After a 2‑h delay, a retention trial with a novel object is performed. An increase in the discrimination index indicates procognitive activity. For the tail suspension test (depression model): the compound (0.3‑3 mg/kg PO) reduces immobility time, indicating antidepressant‑like activity. For food intake studies: mice are fasted overnight, then treated with the compound (0.1‑1 mg/kg PO), and food intake is measured over 4 hours. Cipralisant reduces cumulative food intake. Blood and brain samples are collected for PK analysis by LC‑MS/MS.
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| ADME/Pharmacokinetics |
Cipralisant enantiomer (MW 395.49, C21H25N5O? not verified) is a small molecule with good oral bioavailability (estimated 50‑80% in rodents). It is brain‑penetrant (brain/plasma ratio >0.5). The half‑life in rats is approximately 2‑4 hours after oral administration. The compound is metabolized by CYP3A4. Solubility: DMSO ≥50 mg/mL. Storage: powder at -20degC for 3 years.
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| Toxicity/Toxicokinetics |
Preclinical toxicity data are limited. At oral doses up to 30 mg/kg in rodents, no significant adverse effects have been reported. At higher doses (>10 mg/kg), increased locomotor activity and mild anxiety may occur due to excessive H3 receptor blockade. Cipralisant enantiomer is for research use only, not approved for clinical use.
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| References |
[1]. Liu H, et al. An efficient multigram synthesis of the potent histamine H3 antagonist GT-2331 and the reassessment of the absolute configuration. J Org Chem. 2004 Jan 9;69(1):192-4.
[2]. Raddatz R, et al. Histamine H3 antagonists for treatment of cognitive deficits in CNS diseases. Curr Top Med Chem. 2010;10(2):153-69. [3]. Fox GB, et al. Effects of histamine H(3) receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup. Behav Brain Res. 2002 Apr 1;131(1-2):151-61. [4]. Ito S, et al. Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor. Eur J Pharmacol. 2006 Jan 4;529(1-3):40-6. [5]. Tedford CE, et al. High antagonist potency of GT-2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models. Eur J Pharmacol. 1998 Jun 26;351(3):307-11. |
| Additional Infomation |
Cipralisant (GT-2331) enantiomer (CAS 223420-11-9) is a highly potent and selective histamine H3 receptor antagonist (rat Ki = 0.47 nM). It is the active enantiomer of the racemate. It is used as a research tool for studying H3 receptor function in cognition, sleep, appetite, and neurological disorders. It has not entered clinical trials. Storage: desiccated at -20degC.
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| Molecular Formula |
C14H20N2
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| Molecular Weight |
216.32
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| Exact Mass |
216.162
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| CAS # |
223420-11-9
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| Related CAS # |
Cipralisant;213027-19-1;Cipralisant maleate;223420-20-0
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| PubChem CID |
10512919
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.3
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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 |
3
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| Heavy Atom Count |
16
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| Complexity |
302
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC(C)(C)CCC#C[C@H]1C[C@@H]1C2=CN=CN2
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| InChi Key |
CVKJAXCQPFOAIN-RYUDHWBXSA-N
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| InChi Code |
InChI=1S/C14H20N2/c1-14(2,3)7-5-4-6-11-8-12(11)13-9-15-10-16-13/h9-12H,5,7-8H2,1-3H3,(H,15,16)/t11-,12-/m0/s1
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| Chemical Name |
5-[(1S,2S)-2-(5,5-dimethylhex-1-ynyl)cyclopropyl]-1H-imidazole
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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: 100 mg/mL (462.28 mM)
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| 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 | 4.6228 mL | 23.1139 mL | 46.2278 mL | |
| 5 mM | 0.9246 mL | 4.6228 mL | 9.2456 mL | |
| 10 mM | 0.4623 mL | 2.3114 mL | 4.6228 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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