title: Synthesis and anticonvulsant activity of a class of 2-amino 3-hydroxypropanamide and 2-aminoacetamide derivatives.
abstract: Several studies have demonstrated that N-substituted amino acid derivatives exhibit weak anticonvulsant activities in vivo. In the present study, a series of amides of aminoacids structurally related to aminoacetamide have been synthesised and investigated for anticonvulsant activity. Among the molecules investigated, those containing a bicyclic (tetralinyl, indanyl) group linked to the aminoacetamide chain (40, 47 and 59) were among the most active as anticonvulsants (ED50 > 10, <100 mg/kg after oral administration) against tonic seizures in the mouse maximal electroshock, bicuculline and picrotoxin tests at doses devoid of neurotoxic activity. Altogether, these results suggest the described compounds as a class of orally available anticonvulsants. The ability of these compounds to partially block veratridine-induced aspartate efflux from rat cortical synaptosomes suggests that their anticonvulsant activity may be only partly the consequence of an interaction with neuronal voltage-dependent sodium channels. Some of the most potent compounds appear worthy of a further investigation aimed at assessing their anticonvulsant activity in other models and at elucidating the underlying mechanism of action.
authors.affiliation: R&D Department, Chiesi Farmaceutici S.p.a., Via Palermo 26/A, 43100 Parma, Italy. E.Ghidini@chiesigroup.com
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ghidini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delcanale
authors.forename: Renato
authors.initials: R
authors.lastname: De Fanti
authors.forename: Andrea
authors.initials: A
authors.lastname: Rizzi
authors.forename: Manuela
authors.initials: M
authors.lastname: Mazzuferi
authors.forename: Donata
authors.initials: D
authors.lastname: Rodi
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
authors.forename: Milco
authors.initials: M
authors.lastname: Lipreri
authors.forename: Franco
authors.initials: F
authors.lastname: Bassani
authors.forename: Loredana
authors.initials: L
authors.lastname: Battipaglia
authors.forename: Marco
authors.initials: M
authors.lastname: Bergamaschi
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D015394:Molecular Structure; D012640:Seizures / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D000081:Acetamides; D000577:Amides; D000927:Anticonvulsants