| Size | Price | Stock | Qty |
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| Targets |
Pagoclone acts as a ligand at the benzodiazepine binding site of the GABAA receptor. It binds primarily to GABAA receptors containing α1, α2, α3, or α5 subunits. Pagoclone is a partial agonist at α1-, α2-, and α5-containing receptors and a full agonist at receptors containing the α3 subunit. This receptor subtype selectivity is responsible for its anxiolytic effects with a potentially reduced sedative profile.
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| ln Vitro |
The affinity of goclone for recombinant human GABAA receptors with α1, α2, α3, or α5 subunits is high and about similar (Ki = 0.7-9.1 nM). With an EC50 of 3.1-6.6 nM, pagoclone has strong agonist action at all four diazepam-sensitive GABAA receptor subtypes [1].
Pagoclone demonstrates high and approximately equivalent affinity (Ki values = 0.7-9.1 nM) for recombinant human GABAA receptors containing α1, α2, α3, or α5 subunits. It exhibits significant agonist activity at all four diazepam-sensitive GABAA receptor subtypes, with EC50 values ranging from 3.1 to 6.6 nM. These in vitro binding data confirm its potent and subtype-selective interaction with the GABAA receptor complex. |
| ln Vivo |
At all three tested doses (0.3, 1, and 3 mg/kg, po), goclone dramatically decreased total distance walked, although it also demonstrated considerable anxiolytic-like effects. Arm open time increased dose-dependently when compared to controls when using pagoclone (3 mg/kg, po). In response sensitivity tests, the cumulative chain pull reaction is decreased by pagoclone (1, 3, or 10 mg/kg). The concentrations of paragolone in plasma were shown to be dose-dependent and non-linear, with values of 0.4±0.1, 1.1±0.2, and 2.2±0.2 ng/mL, respectively. In rats, dosage-dependent reductions in locomotor activity are observed with goclone (0.3, 1 or 3 mg/kg) [1].
Pagoclone (3 mg/kg, p.o.) produces significant anxiolytic-like activity in animal models. At doses of 0.3, 1, and 3 mg/kg (p.o.), it causes a significant reduction in total distance travelled, indicating locomotor effects. The compound produces a dose-dependent increase in time spent on open arms in the elevated plus maze test. In the response sensitivity test, Pagoclone (1, 3, or 10 mg/kg) lowers the cumulative chain-pulling response. Plasma concentrations are dose-dependent but not linear (0.4±0.1, 1.1±0.2, and 2.2±0.2 ng/mL at tested doses). |
| Enzyme Assay |
In vitro receptor binding assays are performed using recombinant human GABAA receptors expressed in suitable cell lines. Membrane preparations are incubated with radiolabeled ligands (e.g., [³H]flumazenil or [³H]Ro15-1788) at the benzodiazepine binding site in the presence of varying concentrations of Pagoclone. Non-specific binding is determined using excess unlabeled ligand. Incubations are typically carried out at room temperature for 60-90 minutes, followed by rapid filtration through glass fiber filters. Bound radioactivity is measured by liquid scintillation counting. Ki values are calculated from competition binding curves using appropriate software.
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| Cell Assay |
For in vitro cell-based functional assays, cells expressing recombinant human GABAA receptors of defined subunit compositions (α1β3γ2, α2β3γ2, α3β3γ2, or α5β3γ2) are utilized. Cells are loaded with a membrane potential-sensitive dye or a calcium-sensitive fluorescent indicator. Pagoclone is applied at various concentrations (typically 0.01-1000 nM), and receptor activation is measured as changes in fluorescence intensity using a fluorescence plate reader. EC50 values for agonist activity are determined from concentration-response curves. Data are normalized to the maximal response elicited by a full agonist such as diazepam or GABA.
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| Animal Protocol |
In vivo animal studies are conducted using adult male PVG rats (250-300 g, n=12/group) in the rat chain-pulling assay, a test for sedation. Food-deprived rats are trained on a random probability interval schedule of 60 seconds. Following training, animals receive oral doses of Pagoclone (0.3, 1, or 3 mg/kg) or vehicle (0.5% methylcellulose). The cumulative chain-pulling response is recorded as a measure of sedation. Additionally, the elevated plus maze test is used to assess anxiolytic activity, measuring the time spent in open arms and total distance travelled. Locomotor activity is monitored in an open field apparatus.
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| ADME/Pharmacokinetics |
Pagoclone is administered orally and shows dose-dependent but non-linear plasma concentrations. The compound is soluble in DMSO (10 mg/mL, 24.52 mM) for in vitro preparations. For in vivo administration, it can be formulated as a suspension in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline (1 mg/mL, 2.45 mM) or as a clear solution in 10% DMSO + 90% corn oil (≥1 mg/mL). The half-life and detailed metabolic pathway have not been fully characterized in the available literature.
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| Toxicity/Toxicokinetics |
Specific toxicity data for Pagoclone are not extensively detailed in the available literature. As a GABAA receptor modulator, it is expected to share some pharmacological properties with other cyclopyrrolones. The compound was never commercialised, which may suggest that its development was discontinued due to efficacy, safety, or commercial considerations. Standard preclinical toxicology studies would typically include assessments of acute toxicity, repeated-dose toxicity, genotoxicity, and reproductive toxicity, but specific results are not provided in the available references.
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| References | |
| Additional Infomation |
Pagoclone is a cyclopyrrolidone anxiolytic, belonging to the same class as other more well-known drugs such as zopiclone. It belongs to a relatively new class of drugs—non-benzodiazepines—which have similar efficacy to older benzodiazepines but with significantly different chemical structures. Drug Indications: Used to treat panic disorder and anxiety disorders. Mechanism of Action: Pagoclone is a subtype-selective drug, primarily binding to the α2/α3 subtypes of the GABAA receptor, which are the main mechanisms by which this class of drugs exert their anxiolytic effect. Its efficacy against the α1 subtype, which produces sedation and memory loss, is relatively weak. Pharmacodynamics: Pagoclone was initially developed as an anxiolytic but was never marketed. It is a partial agonist of the GABAA receptor in the brain. Unlike zopiclone, agoclone produces anxiolytic effects at low doses with little or no sedation or amnesia.
Pagoclone was originally developed as an anti-anxiety drug but was never commercialised. It belongs to the nonbenzodiazepine class of anxiolytics, which have similar effects to benzodiazepines but with different chemical structures. The compound's unique profile as a partial agonist at GABAA receptors, particularly its full agonist activity at α3-containing receptors and partial agonism at α1-containing receptors, was intended to provide anxiolytic efficacy with reduced sedation and dependence liability. Clinical development was ultimately discontinued. No approved status or ongoing clinical trials are reported. |
| Molecular Formula |
C23H22CLN3O2
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|---|---|
| Molecular Weight |
407.898
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| Exact Mass |
407.14
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| CAS # |
133737-32-3
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| PubChem CID |
131664
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| Appearance |
White to off-white solid powder
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| Density |
1.273g/cm3
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| Boiling Point |
582.1ºC at 760mmHg
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| Flash Point |
305.9ºC
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| Vapour Pressure |
1.53E-13mmHg at 25°C
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| Index of Refraction |
1.625
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| LogP |
5.445
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
613
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HIUPRQPBWVEQJJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H22ClN3O2/c1-14(2)7-10-16(28)13-19-17-5-3-4-6-18(17)23(29)27(19)21-12-9-15-8-11-20(24)25-22(15)26-21/h3-6,8-9,11-12,14,19H,7,10,13H2,1-2H3
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| Chemical Name |
2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-3H-isoindol-1-one
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| Synonyms |
IP-456; CI-1043; Pagoclone
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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 : ~10 mg/mL (~24.52 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 1 mg/mL (2.45 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (2.45 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 10.0 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 | 2.4516 mL | 12.2579 mL | 24.5158 mL | |
| 5 mM | 0.4903 mL | 2.4516 mL | 4.9032 mL | |
| 10 mM | 0.2452 mL | 1.2258 mL | 2.4516 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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