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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Agonists and antagonists for P2 receptors
Kenneth A Jacobson1, Stefano Costanzi, Bhalchandra V Joshi
1Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
Novartis Foundation Symposium
|June 30, 2006
Summary
Researchers developed novel nucleotide and non-nucleotide molecules targeting P2Y and P2X receptors. Conformational analysis of ribose-like moieties enhanced ligand potency and selectivity for specific P2 receptors.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Molecular Biology
Background:
- P2Y and P2X receptors are crucial drug targets.
- Selective agonists and antagonists for various P2 receptors have been identified.
- Non-nucleotide antagonists offer improved selectivity and properties.
Purpose of the Study:
- To synthesize and characterize novel nucleotide and non-nucleotide ligands for P2Y and P2X receptors.
- To investigate the impact of ribose moiety conformation on ligand activity.
- To enhance potency and selectivity of P2 receptor modulators.
Main Methods:
- Synthesis of nucleotide analogues with modified ribose moieties.
- Structure-activity relationship (SAR) studies.
- Receptor binding and functional assays.
- Computational modeling and mutagenesis studies.
Main Results:
- Selective agonists for P2Y1, P2Y2, and P2Y6 receptors were identified.
- Selective antagonists for P2Y1, P2Y12, P2X1, P2Y13, P2X(2/3)/P2X3, and P2X7 receptors were developed.
- Conformationally locked analogues showed enhanced potency and selectivity.
- (N)-methanocarba analogues demonstrated high affinity and selectivity for P2Y1 receptors.
- P2Y6 receptor activity favored the South conformation.
Conclusions:
- Novel ligands with improved potency and selectivity for P2 receptors were developed.
- Conformational analysis of the ribose-like moiety is key for designing effective P2 receptor modulators.
- Further structural studies of P2Y receptors can guide future drug design.
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