Ibotenic acid analogues. Synthesis and biological testing of two bicyclic 3-isoxazolol amino acids.
The bicyclic 3-isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (5, 4-HPCA) and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-6-carboxylic acid (11, 6-HPCA) were synthesized as model compounds for studies of the structural requirements of central excitatory amino acid neurotransmitter receptors. 4-HPCA was synthesized via introduction of a methoxycarbonyl group into the 4-position of the lithiated N-nitroso intermediate 1. The key reaction in the synthesis of 6-HPCA is an intramolecular N-alkylation of the appropriately substituted acetamidomalonate derivative 7 using sodium hydride as a base. On the basis of the pKA values for 4-HPCA the existence of an intramolecular hydrogen bond in the zwitterionic form of this amino acid is proposed. 6-HPCA was shown by 1H NMR spectroscopy to adopt preferentially a conformation with the carboxylate group in an equatorial position. 4- and 6-HPCA were tested as agonists and antagonists at excitatory amino acid receptors on neurones in the cat spinal cord using microelectrophoretic techniques. Neither compound showed significant effects at these receptors.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002415:Cats; D055598:Chemical Phenomena; D002621:Chemistry; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D007395:Interneurons / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D010080:Oxazoles; C048367:3-hydroxy-4,5,6,7-tetrahydro-isoxazolo(4,5-c)pyridine-4-carboxylic acid; C048368:3-hydroxy-4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridine-6-carboxylic acid; D007051:Ibotenic Acid