Anticonvulsant preclinical profile of CHF 3381: dopaminergic and glutamatergic mechanisms.
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.
Gandolfi
O
O
Department of Pharmacology, University of Bologna, via Irnerio 48, 40126, Bologna, Italy. gandolfi@biocfarm.unibo.it
Bonfante
V
V
Voltattorni
M
M
Dall'Olio
R
R
Poli
A
A
Pietra
C
C
Villetti
G
G
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D007189:Indans / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D000927:Anticonvulsants; D007189:Indans; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005998:Glycine; D004298:Dopamine; C431890:indantadol