RESUMO
A series of conformationally restricted Gabapentin analogues has been synthesised. The pyrrolidine analogue (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride (3a) had an IC50 of 120 nM, similar to that of Gabapentin (IC50 = 140 nM), at the Gabapentin binding site on the alpha2delta subunit of a calcium channel. Compound (3a) also reversed carrageenan induced hyperalgesia in rats.
Assuntos
Acetatos/química , Aminas , Ácidos Cicloexanocarboxílicos , Ácido gama-Aminobutírico , Acetatos/síntese química , Acetatos/farmacologia , Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/farmacologia , Animais , Convulsivantes/síntese química , Convulsivantes/farmacologia , Gabapentina , Estrutura Molecular , RatosRESUMO
Conformational analysis of constrained cyclohexane systems was pioneered fifty years ago by Barton and Hassel. We now report an investigation based on a conformational analysis of a number of novel cyclohexane based Gabapentin analogues coupled with their in vitro evaluation at the Gabapentin binding site. These data are used to propose a possible binding conformation for Gabapentin.
Assuntos
Acetatos/química , Aminas , Anticonvulsivantes/química , Ácidos Cicloexanocarboxílicos , Acetatos/síntese química , Canais de Cálcio/química , Cristalografia por Raios X , Gabapentina , Isomerismo , Espectroscopia de Ressonância Magnética , Modelos Químicos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Temperatura , Ácido gama-Aminobutírico/químicaRESUMO
In order to develop new specific glutamate analogues at metabotropic glutamate receptors, Diels-Alder, 1-4 ionic and radical reactions were performed starting from (2S)-4-methyleneglutamic acid. Preliminary pharmacological evaluation by measuring IP accumulation using rat forebrain synaptoneurosomes has shown that (2S)-4-(2-phthalimidoethyl)glutamic acid (3a), (2S)-4-(4-phthalimidobutyl)glutamic acid (3b) and 1-[(S)-2-amino-2-carboxyethyl]-3,4-dimethylcyclohex-3-ene-1-carbox ylic acid (8) presented moderate antagonist activities.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Ácido Glutâmico/análogos & derivados , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/síntese química , Ácido Glutâmico/farmacologia , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Ratos , Sinaptossomos/efeitos dos fármacosRESUMO
A short synthesis of 4-methylene glutamic acid was achieved. Under thermal conditions the corresponding anhydride reacted with 2,3 dimethylbutadiene to afford the corresponding DIELS-ALDER adduct in good yield. L-4-methylene glutamic acid essentially acts on glutamate metabotropic receptors and is as potent as L-Glu in producing IPs.
