Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)

Pushkar M. Kulkarni, Abhijit R. Kulkarni, Anisha Korde, Ritesh B. Tichkule, Robert B. Laprairie, Eileen M. Denovan-Wright, Han Zhou, David R. Janero, Nikolai Zvonok, Alexandros Makriyannis, Maria G. Cascio, Roger G. Pertwee, Ganesh A. Thakur*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)44-60
Number of pages17
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
Early online date3 Nov 2015
DOIs
Publication statusPublished - 14 Jan 2016

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