Anticonvulsant preclinical profile of CHF 3381: Dopaminergic and glutamatergic mechanisms

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2001-09, Vol.70 (1), p.157-166
• Main Authors: Gandolfi, Ottavio, Bonfante, Veronica, Voltattorni, Manuela, Dall'Olio, Rossella, Poli, Alessandro, Pietra, Claudio, Villetti, Gino
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants; Anticonvulsants - metabolism; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Behavior; Behavior, Animal - drug effects; Behavior, Animal - physiology; Biological and medical sciences; Cells, Cultured; Cerebral Cortex - metabolism; CHF 3381; Dopamine (DA); Dopamine - physiology; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electric Stimulation; Glutamic Acid - metabolism; Glutamic Acid - physiology; Glycine - analogs & derivatives; Glycine - metabolism; Glycine - pharmacology; Indans - metabolism; Indans - pharmacology; Male; Medical sciences; Neuropharmacology; Neurotoxicity; Pharmacology. Drug treatments; Primary cell cultures; Radioligand binding assays; Rat; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(01)00591-3

Following intraperitoneal or oral administrations, CHF 3381 ([ n-(2-indanyl)-glycinamide hydrochloride]) protected rats against maximal electroshock (MES) test seizures. As glutamatergic pathways play a pivotal role in epilepsy, to better characterize the molecular mechanisms of action of CHF 3381, the drug effects on the binding of the excitatory amino acid antagonist [ 3H]-MK-801 in the presence of n-methyl- d-aspartate (NMDA), spermidine, or the combination of both ligands, were studied. CHF 3381 inhibited the [ 3H]-MK-801 specific binding in a noncompetitive fashion in respect to NMDA and polyamines recognition sites. CHF 3381 failed to change the kinetic characteristic of glycine B receptors labeled with [ 3H]-glycine; in contrast, it significantly increased K d values when the receptors were labeled with the more specific compound [ 3H]-MDL 105,519. CHF 3381 antagonized dopamine (DA)-induced behavioral responses and inhibited, in a glycine-dependent manner, the NMDA-induced [ 3H]-DA release from rat striatal slices, but it failed to change either the kinetic characteristics of D 1, D 2, or D 3 receptors in synaptic plasma membranes (SPM) or the [ 3H]-DA uptake from striatal synaptosomes. Moreover, in primary cell cultures of cortical neurons, this drug exhibited glycine-independent neuroprotective effects against glutamate-induced excitotoxicity. It is concluded that this compound could have a potential use in several disease states where a pathological high level of NMDA receptor activation is thought to occur.