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.
| Original language | English |
|---|---|
| Journal | Farmaco |
| Volume | 57 |
| Issue number | 11 |
| Pages (from-to) | 889-95 |
| ISSN | 0014-827X |
| Publication status | Published - Nov 2002 |
Keywords
- Amino Acids
- Animals
- Binding, Competitive
- Cerebral Cortex
- Cyclization
- Cycloleucine
- Electrophysiology
- Excitatory Amino Acid Antagonists
- Glutamates
- Ligands
- Magnetic Resonance Spectroscopy
- Models, Molecular
- Molecular Conformation
- Rats
- Receptors, AMPA
- Receptors, Glutamate
- Receptors, Kainic Acid
- Receptors, Metabotropic Glutamate
- Receptors, N-Methyl-D-Aspartate
- Stereoisomerism
- gamma-Aminobutyric Acid