title: NMDA receptor agonists derived from ibotenic acid. Preparation, neuroexcitation and neurotoxicity.
abstract: The two heterocyclic aspartic acid and glutamic acid analogues derived from ibotenic acid, (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) have previously been shown to be selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively. Two analogous series of AMAA and AMPA derivatives have now been synthesized and characterized in receptor binding studies and neuropharmacological experiments. AMAA was shown to be a very potent NMDA agonist in cortical tissue preparations, slightly more active than NMDA, whereas N-methyl-AMAA was less potent and N,N-dimethyl-AMAA almost inactive. (RS)-3-Hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (4-HPCA), a bicyclic analogue of AMAA, exhibited weak NMDA agonist effects similar to those of quinolinic acid. The relative potency as AMPA receptor agonists of AMPA, N-methyl-AMPA, N,N-dimethyl-AMPA and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA, was distinctly different from that of the AMAA series of compounds as NMDA agonists. The pharmacological and toxicological profiles of AMAA and 4-HPCA, compared with those of quinolinic acid, are consistent with heterogeneity of NMDA receptors.
authors.affiliation: Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
authors.forename: U
authors.initials: U
authors.lastname: Madsen
authors.forename: J W
authors.initials: JW
authors.lastname: Ferkany
authors.forename: B E
authors.initials: BE
authors.lastname: Jones
authors.forename: B
authors.initials: B
authors.lastname: Ebert
authors.forename: T N
authors.initials: TN
authors.lastname: Johansen
authors.forename: T
authors.initials: T
authors.lastname: Holm
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D009420:Nervous System / Q000187:drug effects*; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013268:Stimulation, Chemical; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: D010879:Piperazines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C048367:3-hydroxy-4,5,6,7-tetrahydro-isoxazolo(4,5-c)pyridine-4-carboxylic acid; D007051:Ibotenic Acid; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D002795:Choline O-Acetyltransferase