Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists

Br J Pharmacol. 2003 Mar;138(6):1093-100. doi: 10.1038/sj.bjp.0705148.


1. The natural product willardiine is an AMPA receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and kainate receptors. Structure-activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the antagonists at AMPA or kainate receptors. 2. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA receptor antagonist activity. To examine antagonist activity at kainate receptors, the ability of compounds to depress kainate-induced depolarisations of dorsal root fibres was assessed. 3. Blocking ionisation of the uracil ring by adding a methyl group to the N(3) position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N(3)-position of the uracil ring could antagonise AMPA and kainate receptors. 4. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC(50) values of 287+/-41, 23.8+/-3.9 and 136+/-17 micro M, respectively). For kainate receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root kainate responses with apparent K(D) values of 73.1+/-4.5 and 60.5+/-4.1 micro M, respectively). 5. Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at kainate receptors (UBP291 and UBP301 antagonised kainate responses on the dorsal root with apparent K(D) values of 9.83+/-1.62 and 5.94+/-0.63 micro M, respectively). 6. The most useful antagonist identified in this study was UBP301, which was a potent and approximately 30-fold selective kainate receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated kainate response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / agonists*
  • Alanine / analogs & derivatives*
  • Alanine / analysis
  • Alanine / chemical synthesis*
  • Animals
  • Animals, Newborn
  • Drug Antagonism
  • Evoked Potentials / physiology
  • Molecular Conformation
  • Molecular Structure
  • Nerve Fibers, Unmyelinated / drug effects
  • Pyrimidinones
  • Rats
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / drug effects*
  • Receptors, Kainic Acid / antagonists & inhibitors*
  • Receptors, Kainic Acid / drug effects*
  • Spinal Cord / drug effects
  • Spinal Cord / physiology
  • Spinal Nerve Roots / anatomy & histology*
  • Spinal Nerve Roots / drug effects
  • Spinal Nerve Roots / physiology
  • Structure-Activity Relationship*
  • Uracil


  • Pyrimidinones
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • willardiine
  • Uracil
  • Alanine