Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)
| Autor: | Eileen M. Denovan-Wright, Nikolai Zvonok, David R. Janero, Alexandros Makriyannis, Han Zhou, Maria Grazia Cascio, Robert B. Laprairie, Ganesh A. Thakur, Ritesh B. Tichkule, Abhijit R. Kulkarni, Anisha Korde, Roger G. Pertwee, Pushkar M. Kulkarni |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular Cannabinoid 1 receptor Allosteric modulator Indoles Stereochemistry medicine.drug_class Arrestins Pyridines Allosteric regulation CHO Cells Ligands 03 medical and health sciences Radioligand Assay Structure-Activity Relationship Cricetulus Piperidines Receptor Cannabinoid CB1 Cricetinae Drug Discovery medicine Cyclic AMP Animals Humans Binding Sites Chemistry Drug discovery Phenylurea Compounds food and beverages Affinity Labels Featured Article Cyclohexanols Rats 030104 developmental biology Covalent bond Guanosine 5'-O-(3-Thiotriphosphate) Electrophile Molecular Medicine Allosteric Site |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Undesirable side effects associated with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R negative allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochemical characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust positive allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs. |
| Databáze: | OpenAIRE |
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