Novel potent anticonvulsant agent containing a tetrahydroisoquinoline skeleton.
In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice, and the 1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl) derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA receptor modulator.
Gitto
Rosaria
R
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy. rgitto@pharma.unime.it
Caruso
Roberta
R
Pagano
Benedetta
B
De Luca
Laura
L
Citraro
Rita
R
Russo
Emilio
E
De Sarro
Giovambattista
G
Chimirri
Alba
A
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009833:Olfactory Pathways / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C514070:1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)-1,2,3,4-tetrahydroisoquinoline; D000927:Anticonvulsants; D007546:Isoquinolines; D010880:Piperidines; D018091:Receptors, AMPA; D044005:Tetrahydroisoquinolines