ACKNOWLEDGMENTS The work was supported by National Institutes of Health grants DA027113 and EY024717 to G.A.T. and DA09158 to A.M. A portion of this work was submitted in 2011 by A. Kulkarni in partial fulfillment of M.S. degree requirements from Northeastern University, Boston, MA.Peer reviewe

Cascio, Maria G.

Denovan-Wright, Eileen M.

Janero, David R.

Korde, Anisha

Kulkarni, Abhijit R.

Kulkarni, Pushkar M.

Laprairie, Robert B.

Makriyannis, Alexandros

Pertwee, Roger G.

Thakur, Ganesh A.

Tichkule, Ritesh B.

Zhou, Han

Zvonok, Nikolai

Journal of Medicinal Chemistry

English

PubMed

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

Pushkar M. Kulkarni (1369035)

Abhijit
R. Kulkarni (1369032)

Anisha Korde (1261515)

Ritesh B. Tichkule (1261512)

Robert B. Laprairie (315471)

Eileen M. Denovan-Wright (315472)

Han Zhou (109068)

David
R. Janero (1261527)

Nikolai Zvonok (309311)

Alexandros Makriyannis (32548)

Maria G. Cascio (1261518)

Roger
G. Pertwee (1261524)

Ganesh A. Thakur (638454)

The Francis Crick Institute

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

Crossref

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

Aberdeen University Research

https://aura.abdn.ac.uk/bitstream/2164/7693/1/acs_2Ejmedchem_2E5b01303.pdf

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

Abstract

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The Francis Crick Institute

Crossref

Aberdeen University Research