Discovery of a novel and highly potent noncompetitive AMPA receptor antagonist.
N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.
Gitto
Rosaria
R
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy.
Barreca
Maria Letizia
ML
De Luca
Laura
L
De Sarro
Giovambattista
G
Ferreri
Guido
G
Quartarone
Silvana
S
Russo
Emilio
E
Constanti
Andrew
A
Chimirri
Alba
A
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008811:Mice, Inbred DBA; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
C470657:2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D008024:Ligands; D018091:Receptors, AMPA; D044005:Tetrahydroisoquinolines