Article date: 1985/5/1
PubMed ID: 2985786
Journal name: Journal of medicinal chemistry (ISSN: 0022-2623)
With use of ibotenic acid as a lead, analogues of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogues of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. On the basis of these studies, 7-HPCA as well as 10 were shown to adopt preferentially conformations with the carboxylate groups in equatorial positions. It is suggested that AMPA, 7-HPCA, and 10 interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.
Author List: Krogsgaard-Larsen P, Brehm L, Johansen J S, Vinzents P, Lauridsen J, Curtis D R
Publication Types: Journal Article; Research Support, Non-U.S. Gov't
Substances mentioned in the article: Amino Acids; Oxazoles; Receptors, AMPA; Receptors, Drug; Receptors, Kainic Acid; Receptors, Neurotransmitter; Ibotenic Acid;
Mesh terms: Amino Acids/chemical synthesis; Animals; Brain/metabolism; Cats; Electrophoresis; Ibotenic Acid/analogs & derivatives; In Vitro Techniques; Models, Molecular; Molecular Conformation; Neurons/drug effects; Oxazoles/chemical synthesis; Quantum Theory; Rats; Receptors, AMPA; Receptors, Drug/drug effects; Receptors, Kainic Acid; Receptors, Neurotransmitter/drug effects; Spinal Cord/drug effects; Structure-Activity Relationship; X-Ray Diffraction;