(3SR,4aRS,6SR,8aRS)-6-(1H-Tetrazol-5-yl)decahydroisoquinoline-3-carboxylic Acid, a Novel, Competitive, Systemically Active NMDA and AMPA Receptor Antagonist

• Published in: Journal of medicinal chemistry Vol. 38; no. 25; pp. 4885 - 4890
• Main Authors: Ornstein, Paul L, Arnold, M. Brian, Allen, Nancy K, Leander, J. David, Tizzano, Joseph P, Lodge, David, Schoepp, Darryle D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.12.1995; Amer Chemical Soc
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Chemistry, Medicinal; Columbidae; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptors, AMPA - antagonists & inhibitors; Receptors, Kainic Acid - drug effects; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Science & Technology; Tetrazoles - chemical synthesis; Tetrazoles - pharmacology; PHENCYCLIDINE-LIKE DRUGS; BINDING; GLUCOSE; BRAIN; METHYL-D-ASPARTATE; Tetrazole derivatives; Isoquinoline derivatives; Nitrogen heterocycle; Rodentia; Glutamate receptor; In vitro; In vivo; α-Aminoacid; Vertebrata; Biological fixation; AMPA receptor; Mammalia; Structure activity relation; Mouse; Animal; Antagonist; NMDA receptor; Chemical synthesis; Enantiomer(-)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00025a005

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole-substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtained from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.