Sulfonylurea receptor (associated with ATP-sensitive K+ channel) (IC50 = 27.2 nM for inhibiting [3H]glibenclamide binding in rat cerebral cortex membranes) [1]
Gliquidone targets the ATP-sensitive potassium (KATP) channel on pancreatic beta cells. It is a potent antagonist of this channel, with an IC50 of 27.2 nM. By binding to the sulfonylurea receptor (SUR) subunit of the KATP channel, it blocks potassium efflux, leading to membrane depolarization and subsequent insulin secretion. This mechanism is characteristic of sulfonylurea drugs.

In vitro activity: Gliquidone is an ATP-sensitive K+ channel antagonist. In mice, gliquidone (10 or 40 μg) antagonized morphine (20 mg/kg) induced hypermotility in a dose-dependent way. These results suggested that ATP-sensitive K+ channels played an important role in morphine-induced hypermotility.

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In vitro, Gliquidone is a potent KATP channel antagonist with an IC50 of 27.2 nM. Its activity in blocking these channels and stimulating insulin secretion has been characterized in various cellular and biochemical assays. These studies confirm its mechanism of action as a KATP channel antagonist.

Gliquidone (0.1–1.0 μg per mouse i.c.v.) prevents antinociception produced by amitriptyline and clomipramine in a dose-dependent manner in male swiss albino mice. Gliquidone (0.06–16 μg per mouse, i.c.v.) antagonizes the antinociception induced by buprenorphine, morphine and methadone. Gliquidone (6 μg per mouse, i.c.v.) prevents the antinociception induced by clonidine (0.125 mg/kg, s.c.) and guanabenz (0.30 mg/kg, s.c.), while a lower dose of gliquidone (3 μg per mouse, i.c.v.) is ineffective. Glurenorm (10 mg/kg) given to the diabetic rats produces significant reductions in blood glucose, nonenzymatic glycosylation, and total protein in the lenses, and significantly increases in glutathione levels in the lenses.

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In vivo, Gliquidone is used clinically to lower blood glucose levels in patients with type 2 diabetes. It is an orally active drug. Studies in male Swiss albino mice have shown that intracerebroventricular (i.c.v.) administration of Gliquidone (0.1–1.0 μg per mouse) dose-dependently prevents the antinociceptive effects produced by amitriptyline and clomipramine. This indicates its activity in the central nervous system.

Membrane preparation: Rat cerebral cortex was homogenized in ice-cold 50 mM Tris-HCl buffer pH 7.4, then centrifuged at 40000g for 10 min. The pellet was washed twice with the same buffer. Binding assay: Membrane suspension (0.4-0.8 mg protein/ml) was incubated with 0.5 nM [3H]glibenclamide and various concentrations of Gliquidone (AR-DF26) (CAS#: 33342-05-1) in 50 mM Tris-HCl buffer pH 7.4 at 25°C for 60 min. Non-specific binding was determined in the presence of 0.1 μM unlabeled glibenclamide. Incubations were stopped by rapid filtration through GF/B filters under vacuum, followed by three washes with ice-cold incubation buffer. Filter-bound radioactivity was counted by liquid scintillation. The IC50 value was calculated using ALLFIT or Ligand programs. Gliquidone inhibited specific [3H]glibenclamide binding with an IC50 of 27.2 nM [1].
Non-cellular enzyme assays for Gliquidone are not typical, as its mechanism involves binding to an ion channel rather than direct enzyme inhibition. However, its binding affinity to the KATP channel can be assessed using radioligand binding assays with membrane preparations from cells expressing the channel.

In vitro cell-based assays for Gliquidone are conducted using pancreatic beta-cell lines. Cells are treated with the compound, and insulin secretion is measured by ELISA. Its effects on KATP channel activity can be assessed using patch-clamp electrophysiology. These experiments confirm its mechanism of action and evaluate its potency.

Mice
10 mg/kg

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In vivo animal studies for Gliquidone are performed in rodent models to evaluate its hypoglycemic and other effects. The compound is administered orally or via injection. Its effects on blood glucose levels and other parameters are measured. Studies have also investigated its antinociceptive effects in mice.

Biological Half-Life
The average terminal half-life is approximately 8 hours (range 5.7–9.4 hours).

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Gliquidone is an orally active compound with a molecular weight of 527.63 g/mol. It is well-absorbed from the gastrointestinal tract. Its pharmacokinetic properties have been studied in clinical settings. It is a prescription drug for the treatment of type 2 diabetes.

Gliquidone has an established safety profile from its clinical use. Common side effects include hypoglycemia and gastrointestinal disturbances. As with all sulfonylureas, it can cause hypoglycemia, especially in patients with renal or hepatic impairment. Comprehensive toxicological data are available from its clinical use. Gliquidone is an approved drug.

Fundam Clin Pharmacol.1991;5(2):107-15;Arzneimittelforschung.1997 Mar;47(3):247-52.

1-Cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea belongs to the isoquinoline class of compounds. Gliquidone is a sulfonylurea drug used to treat type 2 diabetes. It is an ATP-dependent potassium channel (KATP channel) blocker. This blocking effect leads to depolarization, which in turn activates voltage-dependent calcium channels, causing calcium ion influx and ultimately increasing insulin release. Gliquidone is a potent second-generation sulfonylurea with hypoglycemic activity. Like other second-generation compounds, gliquidone has a higher affinity for SUR1 and is more potent than first-generation compounds. Furthermore, this drug also has peroxisome proliferation-activated receptor (PPAR) γ-agonist activity. Drug Indications: For the treatment of type 2 diabetes.

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Mechanism of Action
The mechanism of action of glibenclamide in lowering blood glucose appears to rely on stimulating the release of insulin from functional pancreatic β-cells and increasing the sensitivity of peripheral tissues to insulin. Glibenclamide may bind to ATP-sensitive potassium channel receptors on the surface of pancreatic cells, reducing potassium conductance and leading to cell membrane depolarization. Cell membrane depolarization stimulates the influx of calcium ions through voltage-sensitive calcium channels. The increase in intracellular calcium ion concentration induces insulin secretion.

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Pharmacodynamics
Glibenclamide is a sulfonylurea antidiabetic drug. Diabetic patients lack or have no insulin secreted by the pancreas. Insulin is the primary hormone controlling blood glucose. Glibenclamide is an antidiabetic drug used to treat adult-onset diabetes or non-insulin-dependent diabetes mellitus (NIDDM). Its mechanism of action is to lower blood glucose levels by stimulating the pancreas to produce and release insulin. It also promotes the entry of glucose from the blood into cells that need it.

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Gliquidone (AR-DF26) (CAS#: 33342-05-1) is a second-generation sulfonylurea. In the rat cerebral cortex membrane binding assay, its affinity (IC50 = 27.2 nM) for the [3H]glibenclamide site is lower than that of glibenclamide (1.2 nM) but higher than gliclazide (1.9 μM), tolbutamide (43 μM), and chlorpropamide (116 μM). The order of potency for inhibiting [3H]glibenclamide binding correlates with the known hypoglycemic potencies of these compounds [1].
Gliquidone (Glurenorm) is a sulfonylurea antidiabetic agent used to treat type 2 diabetes. It acts as a potent antagonist of KATP channels, stimulating insulin secretion. It is an approved drug with a well-established clinical profile, available by prescription.

C27H33N3O6S

527.63

527.208

33342-05-1

Gliquidone-d6

91610

White to off-white solid powder

1.3±0.1 g/cm3

180-182 ; 181 °C

1.624

3.11

2

6

7

37

948

0

O=S(C1=CC=C(CCN(C(C(C)(C)C2=C3C=C(OC)C=C2)=O)C3=O)C=C1)(NC(NC4CCCCC4)=O)=O

LLJFMFZYVVLQKT-UHFFFAOYSA-N

InChI=1S/C27H33N3O6S/c1-27(2)23-14-11-20(36-3)17-22(23)24(31)30(25(27)32)16-15-18-9-12-21(13-10-18)37(34,35)29-26(33)28-19-7-5-4-6-8-19/h9-14,17,19H,4-8,15-16H2,1-3H3,(H2,28,29,33)

1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxoisoquinolin-2-yl)ethyl]phenyl]sulfonylurea

Gliquidone; Glurenorm; Beglynor; Glikvidon; Glycvidon; Sanofi Synthelabo brand of gliquidone; Yamanouchi brand of gliquidone; AR-DF 26

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.74 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), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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.

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Solubility in Formulation 2: 2.5 mg/mL (4.74 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.74 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly..

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Solubility in Formulation 4: 2% DMSO +Corn oil : 5mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)