Trapani Giuseppe, Latrofa Andrea, Franco Massimo, Carrieri Antonio, Cellamare Saverio, Serra Mariangela, Sanna Enrico, Biggio Giovanni, Liso Gaetano
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125, Bari, Italy.
Eur J Pharm Sci. 2003 Mar;18(3-4):231-40. doi: 10.1016/s0928-0987(03)00002-2.
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.
合成了含有GABA（1 - 3）或甘氨酸（4 - 6）部分的阿尔皮地姆类似物，并评估了它们在中枢（CBR）和外周（PBR）水平与GABA/苯二氮䓬受体复合物的相互作用。特别地，评估了它们调节[3H]-GABA与大鼠大脑皮质洗涤膜制剂特异性结合的能力，以及它们对非洲爪蟾卵母细胞中人类重组GABA(A)受体的影响。这些体外试验的结果表明，活性最高的化合物是1和4。以150 mg/kg的剂量腹腔注射化合物1可显著拮抗大鼠戊四氮诱导的惊厥，保护作用在90分钟内明显。然而，化合物4未能与士的宁敏感的甘氨酸结合位点相互作用。与这些结合结果一致，以150 mg/kg腹腔注射化合物4对士的宁诱导的惊厥没有影响，除了惊厥潜伏期延长。所获得的结果表明，化合物1具有有趣的抗惊厥活性，作为一种新型亲脂性GABA衍生物值得进一步研究。
