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

doi:10.1021/JM050584L

Paper

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

Published Nov 5, 2005 · Nigel P. Dolman, Helen M Troop, Julia C. A. More

Journal of medicinal chemistry

Q1 SJR score

49

Citations

4

Influential Citations

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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.

Study Snapshot

Willardiine derivatives with N3-4-carboxybenzyl substituents show potential as potent and selective kainate receptor antagonists, with potential applications in neuroprotection and neurodegeneration.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

Citations

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

Recent advances in kainate receptor antagonists show potential therapeutic applications in conditions like anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine.

Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid

Willardiine and its synthetic analogues are potential neurodrugs and have applications in peptide chemistry, including diagnostics, protein-nucleic acid interaction, and nanotechnology.

Synthesis and Characterization of Dihydrouracil Analogs Utilizing Biginelli Hybrids

This study presents an innovative, fast, and effective method for synthesizing novel dihydrouracil analogs using Biginelli hybrids, leading to moderate-to-high yields (32-99%).

Long-term effect of neonatal antagonism of ionotropic glutamate receptors on dendritic spines and cognitive function in rats

Blocking neonatal ionotropic glutamate receptors in rats leads to reduced short and long-term memory, altered dendritic spine dynamics, and altered synaptic protein levels in adulthood.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Understanding the structure, function, and pharmacology of glutamate receptors will advance our understanding of brain function and provide new treatment opportunities for neurological diseases.

Kainate and AMPA receptors in epilepsy: Cell biology, signalling pathways and possible crosstalk

Epilepsy is linked to alterations in kainate and AMPA receptors, which play a crucial role in seizure activity and their regulation is affected by seizure activity.

Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD

Sustained activation of kainate receptors leads to long-term depression in hippocampal neurons, demonstrating that KARs bidirectionally regulate synaptic AMPARs and synaptic plasticity.

New insight into nucleo α-amino acids - Synthesis and SAR studies on cytotoxic activity of β-pyrimidine alanines.

Willardiine and its analogs show antiproliferative activity against cancer cells, with potential for treating brain tumors and glioblastoma.

Two new pyrrolidine alkaloids from the red alga Acanthophora spicifera

Two new pyrrolidine alkaloids, acanthophoraines B and C, were isolated from the red alga Acanthophora spicifera, with known ones (3-7) and their antibacterial activities evaluated.