Synthesis and pharmacology of 3-hydroxy-delta2-isoxazoline-cyclopentane analogues of glutamic acid
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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 |
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Journal | Farmaco |
Volume | 57 |
Issue number | 11 |
Pages (from-to) | 889-95 |
ISSN | 0014-827X |
Publication status | Published - Nov 2002 |
- 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
Research areas
ID: 45613736