Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors

Autor:	David Bleakman, Nigel P. Dolman, Samantha Jack, David E Jane, Richard M. Morley, Julia C. A. More, Andrew Alt, Zuner A. Bortolotto, Robert Nisticò, Peter J. Roberts, Helen M Troop, Jody L. Knauss, Graham L. Collingridge
Rok vydání:	2005
Předmět:	Long-Term Potentiation Kainate receptor Alanine Animals Animals Newborn Calcium Cell Line Humans In Vitro Techniques Mossy Fibers Hippocampal Nerve Fibers Unmyelinated Protein Subunits Pyrimidinones Radioligand Assay Rats Receptors AMPA Receptors Kainic Acid Recombinant Proteins Spinal Cord Spinal Nerve Roots Stereoisomerism Structure-Activity Relationship Uracil Pharmacology chemical synthesis/chemistry/pharmacology Nerve Fibers Drug Discovery Receptors AMPA Hippocampal Receptor Unmyelinated Kainic Acid Chemistry Settore BIO/14 Glutamate receptor Long-term potentiation analogs /&/ derivatives/chemical synthesis/chemistry/pharmacology Molecular Medicine Agonist medicine.drug_class Stereochemistry AMPA receptor analogs /&/ derivatives/chemical synthesis/chemistry/pharmacology Animals Animals Newborn Calcium metabolism Cell Line Humans Long-Term Potentiation drug effects Mossy Fibers drug effects/physiology Nerve Fibers drug effects/physiology Protein Subunits antagonists /&/ inhibitors/physiology Pyrimidinones chemical synthesis/chemistry/pharmacology Radioligand Assay Rats Receptors antagonists /&/ inhibitors/physiology Receptors antagonists /&/ inhibitors/physiology Recombinant Proteins metabolism Spinal Cord drug effects/physiology Spinal Nerve Roots drug effects/physiology Stereoisomerism Structure-Activity Relationship Uracil medicine Mossy Fibers antagonists /&/ inhibitors/physiology Antagonist Newborn drug effects/physiology drug effects Enantiomer metabolism
Zdroj:	Journal of medicinal chemistry. 48(24)
ISSN:	0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::251754fe7ba85f935de7c0d98faf024f https://pubmed.ncbi.nlm.nih.gov/16302825 Zobrazit plný text záznamu