title: Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 kainate receptor antagonists.
abstract: Some N3-substituted analogues of willardiine such as 11 and 13 are selective kainate receptor antagonists. In an attempt to improve the potency and selectivity for kainate receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing kainate receptors (KB values of 7 +/- 1 and 5 +/- 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 microM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
authors.affiliation: Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Dolman
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: Olli T
authors.initials: OT
authors.lastname: Pentikäinen
authors.forename: Carla R
authors.initials: CR
authors.lastname: Glasser
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Mark L
authors.initials: ML
authors.lastname: Mayer
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; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; 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; D008024:Ligands; D011744:Pyrimidinones; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; D014498:Uracil; C519517:1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-ylmethyl)-5-methylpyrimidine-2,4-dione; C002872:willardiine