Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid.
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.
Department of Medicinal Chemistry.
Karla
K
Frydenvang
Darryl S
DS
Pickering
Jeremy R
JR
Greenwood
Niels
N
Krogsgaard-Larsen
Lotte
L
Brehm
Birgitte
B
Nielsen
Stine B
SB
Vogensen
Helle
H
Hald
Jette S
JS
Kastrup
Povl
P
Krogsgaard-Larsen
Rasmus P
RP
Clausen
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects*; D018411:Spodoptera; D014982:Xenopus laevis
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D007051:Ibotenic Acid