BIOMAT Database Logo BIOMAT Database Logo

Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists. 2006

Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.

N3-substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and kainate receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and kainate receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLU(K5)-containing kainate receptors (K(D) 0.105 +/- 0.007 microM vs kainate on native GLU(K5); K(D) 71.4 +/- 8.3 microM vs (S)-5-fluorowillardiine on native AMPA receptors). On recombinant human GLU(K5), GLU(K5)/GLU(K6), and GLU(K5)/GLU(K2), K(B) values of 0.12 +/- 0.03, 0.12 +/- 0.01, and 0.18 +/- 0.02 microM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLU(K6) or GLU(K7) kainate receptors or homomeric GLU(A1-4) AMPA receptors (IC(50) values > 100 microM). Thus, 43 is a potent and selective GLU(K5) receptor antagonist.

UI MeSH Term Description Entries
D011744 Pyrimidinones Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O. Pyrimidinone,Pyrimidone,Pyrimidones
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000409 Alanine A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases IMMUNITY, and provides energy for muscle tissue, BRAIN, and the CENTRAL NERVOUS SYSTEM. Abufène,Alanine, L-Isomer,L-Alanine,Alanine, L Isomer,L Alanine,L-Isomer Alanine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor

Related Publications

Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Structure-Activity Relationship and Solubility Studies of N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists.
September 2023, ChemMedChem,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Activation and desensitization of AMPA/kainate receptors by novel derivatives of willardiine.
February 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
AMPA/kainate receptor antagonists as novel analgesic agents.
November 1998, Anesthesiology,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Structure-activity relationship studies of pyrimidine-2,4-dione derivatives as potent P2X7 receptor antagonists.
December 2015, European journal of medicinal chemistry,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship.
January 2023, ACS medicinal chemistry letters,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
3-Substituted phenylalanines as selective AMPA- and kainate receptor ligands.
September 2009, Bioorganic & medicinal chemistry,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
N1H- and N1-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure-Activity Relationship Studies.
June 2021, ACS chemical neuroscience,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Structure-activity relationship analysis of 3-phenylpyrazole derivatives as androgen receptor antagonists.
June 2020, Journal of biomolecular structure & dynamics,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
Structure-activity relationship in N3-alkyl-xanthine derivatives.
April 1988, Japanese journal of pharmacology,
Nigel P Dolman, and Julia C A More, and Andrew Alt, and Jody L Knauss, and Helen M Troop, and David Bleakman, and Graham L Collingridge, and David E Jane
AMPA/kainate glutamate receptor antagonists prevent posttraumatic osteoarthritis.
July 2020, JCI insight,
Copied contents to your clipboard!