Discovery of a novel and highly potent noncompetitive AMPA receptor antagonist

J Med Chem. 2003 Jan 2;46(1):197-200. doi: 10.1021/jm0210008.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • Excitatory Amino Acid Antagonists / chemical synthesis*
  • Excitatory Amino Acid Antagonists / chemistry
  • Excitatory Amino Acid Antagonists / pharmacology
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Ligands
  • Mice
  • Mice, Inbred DBA
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / physiology
  • Seizures / drug therapy
  • Seizures / etiology
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines*

Substances

  • 2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
  • Anticonvulsants
  • Excitatory Amino Acid Antagonists
  • Isoquinolines
  • Ligands
  • Receptors, AMPA
  • Tetrahydroisoquinolines