Alpidem analogues containing a GABA or glycine moiety as new anticonvulsant agents

Alpidem analogues containing a GABA (1-3) or glycine (4-6) moiety were synthesized and their interaction with the GABA/benzodiazepine receptor complex at central (CBR) and peripheral (PBR) level was evaluated. In particular, their ability to modulate the specific binding of [3H]-GABA to washed membrane preparations from the rat cerebral cortex, as well as their effects on human recombinant GABA(A) receptors in Xenopus laevis oocytes, were assessed. Results from these in vitro assays showed that the most active compounds were 1 and 4. Intraperitoneal administration of compound 1 at a dose of 150 mg/kg significantly antagonized pentylenetetrazole-induced seizures in rats and the protective effects were evident for 90 min. However, compound 4 failed to interact with strychnine-sensitive Gly-binding sites. Consistent with these binding results, intraperitoneal administration of compound 4 at 150 mg/kg showed no effect against convulsions induced by strychnine, except for a prolonged time of the latency of convulsions. The results obtained suggest that compound 1 possesses interesting anticonvulsant activity and deserves further investigation as a novel lipophilic GABA derivative.