89017-63-0Relevant academic research and scientific papers
Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid
Frydenvang, Karla,Pickering, Darryl S.,Greenwood, Jeremy R.,Krogsgaard-Larsen, Niels,Brehm, Lotte,Nielsen, Birgitte,Vogensen, Stine B.,Hald, Helle,Kastrup, Jette S.,Krogsgaard-Larsen, Povl,Clausen, Rasmus P.
, p. 8354 - 8361 (2010)
We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.
Ibotenic acid analogues. Synthesis and biological and in vitro activity of conformationally restricted agonists at central excitatory amino acid receptors
Krogsgaard-Larsen,Nielsen,Curtis
, p. 585 - 591 (2007/10/02)
A number of analogues of ibotenic acid [(RS)-3-hydroxy-5-isoxazoleglycine] were synthesized; they were tested as excitants on neurons in the cat spinal cord, by using microelectrophoretic techniques, and as inhibitors of the binding of kainic acid (KA) in vitro, by using synaptic membranes prepared from rat brains. The excitatory effects of the 3-isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (4, 7-HPCA), (RS)-α-amino-3-hydroxy-5,6-dihydro-4H-cyclohept[1,2-d]isoxazole-8-propion ic acid (8, 8-AHCP), (RS)-α-amino-3-hydroxy-7,8-dihydro-6H-cyclohept[1,2-d]isoxazole-4-propion ic acid (12, 4-AHCP), and (RS)-α-(methylamino)-3-hydroxy-5-methyl-4-isoxazolepropionic acid (N-Me-AMPA) were shown to be sensitive to (S)-glutamic acid diethyl ester (GDEE), an antagonist at quisqualic acid (QUIS) receptors, and insensitive to (RS)-2-amino-5-phosphonovaleric acid (2APV), an antagonist at N-methyl-(R)-aspartic acid (NMDA) receptors. The compounds 4 and 12 proved to be particularly potent agonists at the former class of receptor, assumed to represent physiological glutamic acid receptors. The amino acids (RS)-β-(2-carboxyphenyl)alanine (19), an analogue of 12, and (RS)-2-(3-carboxyphenyl)glycine were weak GDEE-sensitive excitants with potencies comparable with that of 8. All of the compounds were tested as inhibitors of KA binding. With the exception of 12 and 19, which showed very low affinity for the KA binding sites, the compounds studied were inactive in this in vitro test system.
