title: Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors.
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.
authors.affiliation: Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Dolman
authors.forename: Helen M
authors.initials: HM
authors.lastname: Troop
authors.forename: Julia C A
authors.initials: JC
authors.lastname: More
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.forename: Jody L
authors.initials: JL
authors.lastname: Knauss
authors.forename: Robert
authors.initials: R
authors.lastname: Nistico
authors.forename: Samantha
authors.initials: S
authors.lastname: Jack
authors.forename: Richard M
authors.initials: RM
authors.lastname: Morley
authors.forename: Zuner A
authors.initials: ZA
authors.lastname: Bortolotto
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000409:Alanine; D002118:Calcium; D021122:Protein Subunits; D011744:Pyrimidinones; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; D014498:Uracil; C507727:1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)-5-iodopyrimidine-2,4-dione; C002872:willardiine