84379-13-5

Bretazenil is a positive allosteric modulator of GABA_A receptors with anticonvulsant and anxiolytic activity. It potentiates GABA-gated chloride currents in rat cortical neurons and in HEK293 cells expressing α₁β₁γ₂ subunit-containing GABA_A receptors (EC₅₀s = 60 and 10 nM, respectively). Bretazenil inhibits binding of the benzodiazepine diazepam to rat cerebral cortex homogenates (IC₅₀ = 2.2 nM). It inhibits tonic convulsions induced by pentylenetetrazol (PTZ; Item No. 18682) and maximal electroshock (MES) in rats (ED₅₀s = 0.07 and 0.48 mg/kg, respectively). Bretazenil (5-30 mg/kg) increases the number of open arm entries and percentage of time spent in the open arms of the elevated plus maze in mice, indicating anxiolytic-like activity.

Bretazenil,Hoffman-La Roche, Inc.

Anti-anxiety agent.

50.6 mmol of 6-bromoisatoic acid anhydride are stirred at 110°C for 2 hours with 50.6 mmol of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallized from ethyl acetate. There is obtained (S)-6-bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1- c][1,4]benzodiazepine-5,11(10H)-dione.
A suspension of 29.8 mmol of sodium hydride (55 percent oil dispersion) in 40 ml of dry dimethylformamide is treated at 20-30°C with 27.1 mmol of (S)-6- bromo-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)- dione, the mixture is stirred in the above temperature range for 45 min and then at -35°C 27.1 mmol of diethylchlorophosphate are added dropwise thereto.
Separately, 3.0 g (27.1 mmol) of potassium t-butylate are dissolved in 9.0 ml of dry dimethylformamide, cooled in an acetone/dry-ice bath, treated with 3.9 g (27.1 mmol) of t-butyl isocyanoacetate and the solution obtained is added dropwise at -15°C to the mixture obtained according to the preceding paragraph. The mixture is warmed to 15°C, neutralized with 1.5 ml of glacial acetic acid, poured into 100 ml of water and extracted four times with methylene chloride. The methylene chloride solution is washed twice with water, dried over magnesium sulfate, evaporated and the crude product obtained is chromatographed on silica gel using ethyl acetate for the elution. By recrystallization from ethyl acetate/n-hexane there is obtained t-butyl (S)- 8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1- c][1,4]benzodiazepine-1-carboxylate.

Anxiolytic

Partial agonist at the GABA A benzodiazepine site (EC 50 = 10 nM at α 1 β 1 γ 2 receptors). Displays anticonvulsive activity in vivo .

Bretazenil exhibits an ticonflflict and anticonvulsant properties. Only mild sedation appears at doses needed to produce anticonvulsant or anxiolytic effects, and potentiation of ethanol-induced sedation is less pronounced than with diazepam.

Desiccate at +4°C