Anticonvulsant preclinical profile of CHF 3381: dopaminergic and glutamatergic mechanisms.

Abstract

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 D1, D2, or D3 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.

• Authors: O Gandolfi, V Bonfante, M Voltattorni, R Dall'Olio, A Poli, C Pietra, G Villetti
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 70 Issue 1 Pg. 157-66 (Sep 2001) ISSN: 0091-3057 [Print] United States
• PMID: 11566153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Indans
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid
• Glycine
• Dopamine
• indantadol

Topics

• Animals
• Anticonvulsants (metabolism, pharmacology)
• Behavior, Animal (drug effects, physiology)
• Cells, Cultured
• Cerebral Cortex (metabolism)
• Dopamine (physiology)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Electric Stimulation
• Glutamic Acid (metabolism, physiology)
• Glycine (analogs & derivatives, metabolism, pharmacology)
• Indans (metabolism, pharmacology)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)