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Purity: ≥98%
Loreclezole (R-72063; R 72063; R72063), a triazole analog, is a sedative, anti-seizure/anticonvulsant and antiepileptic agent that acts as a positive allosteric modulator (PAM) of GABAA receptor. Loreclezole has anti-seizure activity in a variety of seizure models, acting more like a barbiturate than a benzodiazepine in that the increase in seizure threshold produced by loreclezole was potentiated rather than blocked by the benzodiazepine antagonist, flumazenil, confirming that loreclezole does not interact with the benzodiazepine recognition site. In animal seizure models, loreclezole is protective against pentylenetetrazol seizures but is less active in the maximal electroshock test.
| Targets |
GABAA receptor
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|---|---|
| ln Vitro |
Loreclezole, an anticonvulsant and antiepileptic compound, potentiates gamma-aminobutyric acid (GABA) type A receptor function, by interacting with a specific allosteric modulatory site on receptor beta-subunits. A similar selectivity for GABAA receptor beta-subunits is apparent for the direct activation of receptor-operated Cl- channels, by the general anesthetics propofol and pentobarbital. The ability of loreclezole to activate GABAA receptors directly has now been compared, biochemically and electrophysiologically, with that of propofol. In well-washed rat cortical membranes (devoid of endogenous GABA), loreclezole and propofol increased t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding by up to 28% (at 5 microM) and 80% (at 10 microM), respectively. Higher concentrations (50-100 microM) of both compounds inhibited [35S]TBPS binding with great efficacy, an effect mimicked by GABA. In contrast, the benzodiazepine diazepam increased [35S]TBPS binding, but failed to inhibit this parameter, even at high concentrations. At concentrations of 50-100 microM, loreclezole induced inward Cl- currents in the absence of GABA, in Xenopus oocytes expressing human recombinant GABAA receptors, comprised of alpha 1-, beta 2- and gamma 2S-subunits. At 100 microM, the current evoked by loreclezole was 26% of that induced by 5 microM GABA. The current evoked by 100 microM propofol was 98% of that induced by 5 microM GABA. Currents induced by loreclezole, like those evoked by propofol, were potentiated by diazepam in a flumazenil-sensitive manner and blocked by either bicuculline or picrotoxin. These data suggest that loreclezole shares, with propofol, an agonistic action at GABAA receptors containing the beta 2-subunit and that the different efficacies of the two compounds in this regard, may underlie the difference in their pharmacological profiles. The failure of loreclezole to activate GABAA receptors containing the beta 1-subunit may be responsible for its lack of hypnotic effect[2].
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| ln Vivo |
Loreclezole (10, 25, 50, or 75 mg/kg, administered intraperitoneally 60 minutes before epileptic threshold measurement) induced a dose-dependent rise in epileptic threshold, as determined by the dose of pentylenetetrazole necessary to trigger convulsion 60 minutes later. Loreclezole also has negligible effects on loss of muscle tone, as evaluated by the "Pull-Up" test [3].
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| Enzyme Assay |
Type A gamma-aminobutyric acid (GABAA) receptors of the mammalian nervous system are a family of ligand-gated ion channels probably formed from the coassembly of different subunits (alpha 1-6, beta 1-3, gamma 1-3, delta) in the arrangement alpha beta gamma or alpha beta delta. The activation of these receptors by GABA can be modulated by a range of compounds acting at distinct allosteric sites. One such compound is the broad-spectrum anticonvulsant loreclezole, which we have recently shown to act via a specific modulatory site on the beta subunit of the GABAA receptor. The action of loreclezole depends on the type of beta subunit present in the receptor complex; receptors containing beta 2 or beta 3 subunits have > 300-fold higher affinity for loreclezole than receptors containing a beta 1 subunit. We have used this property to identify the amino acid residue in the beta subunit that determines the subunit selectivity of loreclezole. Chimeric beta 1/beta 2 human GABAA receptor subunits were constructed and coexpressed in Xenopus oocytes with human alpha 1 and gamma 2s subunits. The chimera beta 1/beta 2Lys237-Gly334 conferred sensitivity to 1 microM loreclezole. Within this region there are four amino acids that are conserved in beta 2 and beta 3 but differ in beta 1. By mutating single amino acids of the beta 1 subunit to the beta 2/beta 3 equivalent, only the beta 1 mutation of Ser-290-->Asn conferred potentiation by loreclezole. Similarly, mutation of the homologous residue in the beta 2 and beta 3 subunits to the beta 1 equivalent (Asn-->Ser) resulted in loss of sensitivity to loreclezole. The affinity for GABA and the potentiation by flunitrazepam were unchanged in receptors containing the mutated beta subunits. Thus, a single amino acid, beta 2 Asn-289 (beta 3 Asn-290), located at the carboxyl-terminal end of the putative channel-lining domain TM2, confers sensitivity to the modulatory effects of loreclezole[1].
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| Animal Protocol |
Animal/Disease Models: Adult male Lister Hooded rat[3].
Doses: 10, 25, 50 or 75 mg/kg. Route of Administration: IP, 60 minutes before measuring seizure threshold. Experimental Results: Produced a dose-dependent increase in epileptic threshold, as measured by the dose of pentylenetetrazole required to produce convulsion after 60 minutes. Loreclezole is an anticonvulsant and anxiolytic compound which has been reported to potentiate GABA via a novel allosteric site on the beta-subunit of the receptor. We have now studied in rats both the in vivo and in vitro pharmacology of the compound. The dose of loreclezole required to increase by 50% the dose of intravenous pentylenetetrazol eliciting a seizure was comparable to that of barbiturates and chlormethiazole (in mg/kg): diazepam, 1.3; pentobarbitone, 16; chlormethiazole, 22; loreclezole, 25; pentobarbitone, 36. Loreclezole dose-dependently decreased locomotion (dose to decrease locomotion by 50% (in mg/kg): chlormethiazole, 9; pentobarbitone, 16; loreclezole, 25). Loreclezole, chlormethiazole and pentobarbitone all failed to displace [3H]muscimol and [3H]flunitrazepam binding from a rat cortical membrane preparation. All three compounds fully displaced [35S]TBPS binding (IC50 values: loreclezole, 4.34 +/- 0.68 microM; pentobarbitone, 37.39 +/- 3.24 microM; chlormethiazole, 82.10 +/- 8.52 microM). Addition of bicuculline (10 microM) produced a major rightward shift in the loreclezole and pentobarbitone displacement curves, increasing IC50 values for [35S]TBPS binding by 25 times (loreclezole), 6 times (pentobarbitone) and 2.7 times (chlormethiazole), suggesting a greater involvement of GABA in the interaction of loreclezole with the chloride channel than in the case of chlormethiazole. Anticonvulsant activity of the compounds did not appear to relate to [35S]TBPS binding activity. Other binding data suggested that although the evidence of others indicates that loreclezole interacts with a specific allosteric site on the beta-subunit, it nevertheless also alters the binding characteristics of other modulatory sites.[3] |
| References |
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| Additional Infomation |
1-[2-chloro-2-(2,4-dichlorophenyl)ethenyl]-1,2,4-triazole is a dichlorobenzene.
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| Molecular Formula |
C10H6CL3N3
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|---|---|
| Molecular Weight |
274.52
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| Exact Mass |
272.963
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| Elemental Analysis |
C, 43.75; H, 2.20; Cl, 38.74; N, 15.31
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| CAS # |
117857-45-1
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| Related CAS # |
117857-45-1;2227372-56-5 (HCl);
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| PubChem CID |
3034012
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| Appearance |
White to off-white solid powder
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| Density |
1.48g/cm3
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| Boiling Point |
418.7ºC at 760mmHg
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| Flash Point |
207ºC
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| Vapour Pressure |
3.23E-07mmHg at 25°C
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| Index of Refraction |
1.65
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| LogP |
3.779
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
16
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| Complexity |
272
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=C(C=C1Cl)Cl)/C(=C/N2C=NC=N2)/Cl
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| InChi Key |
XGLHZTBDUXXHOM-WMZJFQQLSA-N
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| InChi Code |
InChI=1S/C10H6Cl3N3/c11-7-1-2-8(9(12)3-7)10(13)4-16-6-14-5-15-16/h1-6H/b10-4-
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| Chemical Name |
(Z)-1-(2-chloro-2-(2,4-dichlorophenyl)vinyl)-1H-1,2,4-triazole
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| Synonyms |
R-72063; R 72063; Loreclezole; 117857-45-1; R 72063; R-72063; 6DJ32STZ5W; Loreclezol; (Z)-1-(beta,2,4-Trichlorostyryl)-1H-1,2,4-triazole; (Z)-1-(2-chloro-2-(2,4-dichlorophenyl)vinyl)-1H-1,2,4-triazole; R72063
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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 : ~110 mg/mL (~400.68 mM)
H2O : < 0.1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.58 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 (7.58 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 | 3.6427 mL | 18.2136 mL | 36.4272 mL | |
| 5 mM | 0.7285 mL | 3.6427 mL | 7.2854 mL | |
| 10 mM | 0.3643 mL | 1.8214 mL | 3.6427 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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