Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues of glutamic acid

Farmaco. 2002 Nov;57(11):889-95. doi: 10.1016/s0014-827x(02)01307-1.

Abstract

The synthesis and pharmacology of two potential glutamic acid receptor ligands are described. Preparation of the bicyclic 3-hydroxy-delta2-isoxazoline-cyclopentane derivatives (+/-)-7 and (+/-)-8 was accomplished via 1,3-dipolar cycloaddition of bromonitrile oxide to suitably protected 1-amino-cyclopent-3-enecarboxylic acids. Their structure was established using a combination of 1H NMR spectroscopy and molecular mechanics calculations carried out on the intermediate cycloadducts (+/-)-11 and (+/-)-12. Amino acid derivatives (+/-)-7 and (+/-)-8 were assayed at ionotropic and metabotropic glutamic acid receptor subtypes and their activity compared with that of trans-ACPD and cis-ACPD. The results show that the replacement of the omega-carboxylic group of the model compounds with the 3-hydroxy-delta2-isoxazoline moiety abolishes or reduces drastically the activity at the metabotropic glutamate receptors. Conversely, on passing from cis-ACPD to derivative (+/-)-8, the agonist activity at NMDA receptors is almost unaffected.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Binding, Competitive / drug effects
  • Cerebral Cortex / drug effects
  • Cyclization
  • Cycloleucine / analogs & derivatives*
  • Cycloleucine / chemical synthesis
  • Cycloleucine / pharmacology
  • Electrophysiology
  • Excitatory Amino Acid Antagonists / chemical synthesis
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamates / chemical synthesis*
  • Glutamates / pharmacology*
  • In Vitro Techniques
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Rats
  • Receptors, AMPA / drug effects
  • Receptors, Glutamate / drug effects*
  • Receptors, Kainic Acid / drug effects
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Stereoisomerism
  • gamma-Aminobutyric Acid / physiology

Substances

  • Amino Acids
  • Excitatory Amino Acid Antagonists
  • Glutamates
  • Ligands
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, Kainic Acid
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Cycloleucine
  • 1-amino-1,3-dicarboxycyclopentane
  • gamma-Aminobutyric Acid