title: Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists.
abstract: 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.
authors.affiliation: Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Julia C A
authors.initials: JC
authors.lastname: More
authors.forename: Helen M
authors.initials: HM
authors.lastname: Troop
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Dolman
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
mesh_terms: D000409:Alanine / Q000819:agonists* / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis*; D000818:Animals; D000831:Animals, Newborn; D004336:Drug Antagonism; D005071:Evoked Potentials / Q000502:physiology; D008968:Molecular Conformation; D015394:Molecular Structure; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D011744:Pyrimidinones; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013126:Spinal Nerve Roots / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014498:Uracil
chemical_list: D000409:Alanine; D011744:Pyrimidinones; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D014498:Uracil; C002872:willardiine