Synthesis and Pharmacology of Willardiine Derivatives Acting as Antagonists of Kainate Receptors

• Published in: Journal of medicinal chemistry 2005-12, Vol.48 (24), p.7867-7881
• Main Authors: Dolman, Nigel P, Troop, Helen M, More, Julia C. A, Alt, Andrew, Knauss, Jody L, Nistico, Robert, Jack, Samantha, Morley, Richard M, Bortolotto, Zuner A, Roberts, Peter J, Bleakman, David, Collingridge, Graham L, Jane, David E
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - chemistry; Alanine - pharmacology; Animals; Animals, Newborn; Biological and medical sciences; Calcium - metabolism; Cell Line; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; In Vitro Techniques; Long-Term Potentiation - drug effects; Medical sciences; Mossy Fibers, Hippocampal - drug effects; Mossy Fibers, Hippocampal - physiology; Nerve Fibers, Unmyelinated - drug effects; Nerve Fibers, Unmyelinated - physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Subunits - antagonists & inhibitors; Protein Subunits - physiology; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Radioligand Assay; Rats; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - physiology; Receptors, Kainic Acid - antagonists & inhibitors; Receptors, Kainic Acid - physiology; Recombinant Proteins - metabolism; Spinal Cord - drug effects; Spinal Cord - physiology; Spinal Nerve Roots - drug effects; Spinal Nerve Roots - physiology; Stereoisomerism; Structure-Activity Relationship; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - chemistry; Uracil - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050584l

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 N 3 position of the uracil ring were synthesized. The N 3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLUK5-containing kainate receptors in the neonatal rat spinal cord. The N 3-2-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.