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 (M ES) test seizures. As glutamatergic pathways play a pivotal role in epileps y, to better characterize the molecular mechanisms of action of CBF 3381, t he drug effects on the binding of the excitatory amino acid antagonist [H-3 ]-MK-801 in the presence of n-methyl-D-aspartate (NMDA), spermidine, or the combination of both ligands, were studied. CHF 3381 inhibited the [H-3]-MK -801 specific binding in a noncompetitive fashion in respect to NMDA and po lyamines recognition sites. CHF 3381 failed to change the kinetic character istic of glycine B receptors labeled with [H-3]-glycine; in contrast, it si gnificantly increased K-d values when the receptors were labeled with the m ore specific compound [H-3]-MDL 105,519. CBF 3381 antagonized dopamine (DA) -induced behavioral responses and inhibited, in a glycine-dependent manner, the NMDA-induced [H-3]-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 [H-3]-DA uptake from striatal syn aptosomes. Moreover, in primary cell cultures of cortical neurons, this dru g exhibited glycine-independent neuroprotective effects against glutamate-i nduced excitotoxicity. It is concluded that this compound could have a pote ntial use in several disease states where a pathological high level of NMDA receptor activation is thought to occur. (C) 2001 Elsevier Science Inc. Al l rights reserved.