title: Alpidem analogues containing a GABA or glycine moiety as new anticonvulsant agents.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125, Bari, Italy. trapani@farmchim.uniba.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
authors.forename: Andrea
authors.initials: A
authors.lastname: Latrofa
authors.forename: Massimo
authors.initials: M
authors.lastname: Franco
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.forename: Mariangela
authors.initials: M
authors.lastname: Serra
authors.forename: Enrico
authors.initials: E
authors.lastname: Sanna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
authors.forename: Gaetano
authors.initials: G
authors.lastname: Liso
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry*; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000927:Anticonvulsants; D007093:Imidazoles; D011725:Pyridines; D005680:gamma-Aminobutyric Acid; C052036:alpidem; D005998:Glycine