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 properti...

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Veröffentlicht in:	Journal of medicinal chemistry 2003-01, Vol.46 (1), p.197-200
Hauptverfasser:	Gitto, Rosaria, Barreca, Maria Letizia, De Luca, Laura, De Sarro, Giovambattista, Ferreri, Guido, Quartarone, Silvana, Russo, Emilio, Constanti, Andrew, Chimirri, Alba
Format:	Artikel
Sprache:	eng
Schlagworte:	Acoustic Stimulation Animals Anticonvulsants - chemical synthesis Anticonvulsants - chemistry Anticonvulsants - pharmacology Biological and medical sciences Excitatory Amino Acid Antagonists - chemical synthesis Excitatory Amino Acid Antagonists - chemistry Excitatory Amino Acid Antagonists - pharmacology Glutamatergic system (aspartate and other excitatory aminoacids) Isoquinolines - chemical synthesis Isoquinolines - chemistry Isoquinolines - pharmacology Ligands Medical sciences Mice Mice, Inbred DBA Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Receptors, AMPA - antagonists & inhibitors Receptors, AMPA - physiology Seizures - drug therapy Seizures - etiology Structure-Activity Relationship Tetrahydroisoquinolines
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Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm0210008