2. Academic Validation
  3. Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors

Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors

  • J Med Chem. 2005 Dec 1;48(24):7867-81. doi: 10.1021/jm050584l.
Nigel P Dolman 1,  Helen M Troop,  Julia C A More,  Andrew Alt,  Jody L Knauss,  Robert Nistico,  Samantha Jack,  Richard M Morley,  Zuner A Bortolotto,  Peter J Roberts,  David Bleakman,  Graham L Collingridge,  David E Jane
Affiliations

Affiliation

  • 1 Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol, BS8 1TD, UK.
PMID: 16302825 DOI: 10.1021/jm050584l
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.

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