Document Report Card

ID: ALA1141230

Journal: J Med Chem

Title: Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors.

Authors: Dolman NP, Troop HM, More JC, Alt A, Knauss JL, Nistico R, Jack S, Morley RM, Bortolotto ZA, Roberts PJ, Bleakman D, Collingridge GL, Jane DE.

Abstract: The natural product willardiine (8) is an AMPA receptor agonist while 5-iodowillardiine (10) is a selective kainate receptor agonist. In an attempt to produce antagonists of kainate and AMPA receptors analogues of willardiine with substituents at the N3 position of the uracil ring were synthesized. The N3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLUK5-containing kainate receptors in the neonatal rat spinal cord. The N3-2-carboxybenzyl substituted analogue (38a) proved to be a potent and selective GLUK5 subunit containing kainate receptor antagonist when tested on native rat and human recombinant AMPA and kainate receptor subtypes. The GLUK5 kainate receptor antagonist activity was found to reside in the S enantiomer (44a) whereas the R enantiomer (44b) was almost inactive. 5-Iodo substitution of the uracil ring of 44a gave 45, which was found to have enhanced potency and selectivity for GLUK5.

CiteXplore: 16302825

DOI: 10.1021/jm050584l