Alpidem

Alpidem, an anxiolytic agent, is an orally active and brain-penetrant GABAA receptor ligand, binds to α1β2γ2 subunit-containing GABAA receptors (IC₅₀ of 17 nM) over α5β2γ2 subunit-containing GABAA receptors (IC₅₀ of >10 μM). Alpidem modulates calcium-induced mitochondrial permeability transition, induces glutathione depletion and hepatocyte necrosis, potentiates TNF-α toxicity, inhibits marble-burying and locomotor activity, enhances stressed rodent feeding behavior, and exerts anticonvulsant effects. Alpidem can be used for the research of anxiety, anxiety disorders, and convulsions^{[1][2][3][4][5][6][7][8][9][10][11]}. In Vitro:Alpidem selectively binds to the omega-1 receptor, shows much lower affinity for the omega-2 receptor, and displays extremely high affinity for the omega-3 receptor in rat brain membrane preparations^[1].
Alpidem binds to immobilised Human Serum Albumin with a K_d of 2 μM^[2].
Alpidem (25-500 μM) exerts dual concentration-dependent effects on calcium-induced mitochondrial permeability transition in isolated rat liver mitochondria, accelerating MPT at 25-50 μM and preventing MPT at 250-500 μM, while having no effect on MPT when tested alone without Ca^2+[3].
Alpidem (10-500 μM) induces concentration-dependent toxicity in isolated rat hepatocytes, causing glutathione depletion and necrotic cell death at 250-500 μM (prevented by cystine but not cyclosporin A), glutathione-independent cell death at 25-50 μM (prevented by Cyclosporin A (HY-B0579) but not cystine), and enhanced TNF-α toxicity at 10 μM^[3].
Alpidem exhibits nanomolar binding affinity for both peripheral benzodiazepine receptors (K_i = 0.5-7 nM) and central benzodiazepine receptors (K_i = 1-28 nM) in rat tissue preparations^[4].
Alpidem (increasing concentrations; 60 min at 4°C) displays monophasic displacement of [³H]Flumazenil binding in adult rat cerebellum with an IC₅₀ of 6.3 nM, and triphasic displacement in adult rat hippocampus with high (IC₅₀ 6.3 nM), intermediate (IC₅₀ 122 nM), and low (IC₅₀ 2300 nM) affinity components accounting for 35%, 42%, and 24% of total binding, respectively^[8].
Alpidem binds to both central and peripheral benzodiazepine receptors in rat cerebral cortex membrane preparations^[9]. In Vivo:Alpidem (1-10 mg/kg; p.o.) exhibits anxiolytic activity in select mouse anxiety models, with a profile distinct from benzodiazepines^[1].
Alpidem (20-100 mg/kg; p.o.; i.p.) exerts anxiolytic-like effects in rat anxiety models, with a unique profile compared to benzodiazepines, including lack of anticonflict activity in punished lever-pressing and no benzodiazepine-like discriminative stimulus^[1].
Alpidem (10-30 mg/kg; i.p.) exhibits anticonvulsant activity in multiple mouse convulsion models with ED₅₀ values ranging from 10 mg/kg to 30 mg/kg, and its effects are mediated by central omega receptors as demonstrated by Flumazenil (HY-B0009) antagonism^[1].
Alpidem (8.5-100 mg/kg; i.p.; 40-80 mg/kg; p.o.) induces motor impairment in mice at ED₅₀ values of 70 mg/kg (rotarod) and 100 mg/kg (loaded grid) (i.p.), and impairs memory only at high doses (40-80 mg/kg, p.o.) that also reduce exploratory activity^[1].
Alpidem (3 mg/kg; i.v., p.o.; single dose) shows preferential localization in lipid-rich tissues including the central nervous system, high biliary and fecal excretion, and a terminal plasma half-life of 1.2-1.7 hours in Sprague-Dawley rats^[6].
Alpidem (4 mg/kg; i.p.; single dose) produces a weak anxiolytic effect in the mouse four plates test, significantly increasing punished crossings by 40%^[10].
Alpidem (0.25-8 mg/kg; i.p.; single dose) does not produce significant myorelaxant effects in the mouse rotarod test at doses up to 8 mg/kg, with increased falls at higher doses linked to sedation^[10].
Alpidem (4-32 mg/kg; i.p.; single dose) dose-dependently reduces spontaneous locomotor activity in mice, with significant suppression starting at 8 mg/kg and maximum suppression at 32 mg/kg^[10].
Alpidem (4-32 mg/kg; i.p.; single dose; 30 minutes pre-test) produces a weak anti-conflict effect in the rat operant conflict paradigm only at the highest tested dose of 32 mg/kg, which also causes significant suppression of unpunished lever press performance^[10].