Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

  • J Med Chem. 2010 Dec 9;53(23):8354-61. doi: 10.1021/jm101218a.
Karla Frydenvang  1 ,  Darryl S Pickering ,  Jeremy R Greenwood ,  Niels Krogsgaard-Larsen ,  Lotte Brehm ,  Birgitte Nielsen ,  Stine B Vogensen ,  Helle Hald ,  Jette S Kastrup ,  Povl Krogsgaard-Larsen ,  Rasmus P Clausen
Affiliations
  • 1. Department of Medicinal Chemistry.
PMID: 21067182 DOI: 10.1021/jm101218a
Abstract

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.