Synthesis and anticonvulsant activity of a class of 2-amino 3-hydroxypropanamide and 2-aminoacetamide derivatives.
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.
Ghidini
Eleonora
E
R&D Department, Chiesi Farmaceutici S.p.a., Via Palermo 26/A, 43100 Parma, Italy. E.Ghidini@chiesigroup.com
Delcanale
Maurizio
M
De Fanti
Renato
R
Rizzi
Andrea
A
Mazzuferi
Manuela
M
Rodi
Donata
D
Simonato
Michele
M
Lipreri
Milco
M
Bassani
Franco
F
Battipaglia
Loredana
L
Bergamaschi
Marco
M
Villetti
Gino
G
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*
D000081:Acetamides; D000577:Amides; D000927:Anticonvulsants