RESUMO
Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.
Assuntos
Acetatos/farmacologia , Aminas , Cálcio/metabolismo , Ácidos Cicloexanocarboxílicos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Neocórtex/metabolismo , Neurônios/metabolismo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologia , Adolescente , Adulto , Anticonvulsivantes , Bloqueadores dos Canais de Cálcio/farmacologia , Criança , Pré-Escolar , Feminino , Gabapentina , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Neocórtex/citologia , Neocórtex/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Norepinefrina/metabolismo , Potássio/metabolismo , Pregabalina , Quinoxalinas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , ômega-Agatoxina IVA/farmacologiaRESUMO
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.