Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids

J Med Chem. 2003 Jul 3;46(14):3102-8. doi: 10.1021/jm0308085.

Abstract

Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Acidic / chemical synthesis*
  • Amino Acids, Acidic / chemistry
  • Amino Acids, Acidic / pharmacology
  • Amino Acids, Dicarboxylic / chemical synthesis*
  • Amino Acids, Dicarboxylic / chemistry
  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • CHO Cells
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Crystallography, X-Ray
  • Dicarboxylic Acids / chemical synthesis*
  • Dicarboxylic Acids / chemistry
  • Dicarboxylic Acids / pharmacology
  • Excitatory Amino Acid Agonists / chemical synthesis
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / chemical synthesis
  • Excitatory Amino Acid Antagonists / chemistry
  • Excitatory Amino Acid Antagonists / pharmacology
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • In Vitro Techniques
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Male
  • Mice
  • Mice, Inbred DBA
  • Molecular Conformation
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Stereoisomerism

Substances

  • 5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta(d)isoxazole-3,5-dicarboxylic acid
  • Amino Acids, Acidic
  • Amino Acids, Dicarboxylic
  • Anticonvulsants
  • Dicarboxylic Acids
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Heterocyclic Compounds, 2-Ring
  • Isoxazoles
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor type 1