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

doi:10.1021/acs.jmedchem.5b01303

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	44-60
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	1
Early online date	3 Nov 2015
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01303
Publication status	Published - 14 Jan 2016

Bibliographical note

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.

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Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)
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Kulkarni, P. M., Kulkarni, A. R., Korde, A., Tichkule, R. B., Laprairie, R. B., Denovan-Wright, E. M., Zhou, H., Janero, D. R., Zvonok, N., Makriyannis, A., Cascio, M. G., Pertwee, R. G., & Thakur, G. A. (2016). Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s). Journal of Medicinal Chemistry, 59(1), 44-60. https://doi.org/10.1021/acs.jmedchem.5b01303

Kulkarni, PM, Kulkarni, AR, Korde, A, Tichkule, RB, Laprairie, RB, Denovan-Wright, EM, Zhou, H, Janero, DR, Zvonok, N, Makriyannis, A, Cascio, MG , Pertwee, RG & Thakur, GA 2016, 'Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)', Journal of Medicinal Chemistry, vol. 59, no. 1, pp. 44-60. https://doi.org/10.1021/acs.jmedchem.5b01303

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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.",

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AU - Tichkule, Ritesh B.

AU - Laprairie, Robert B.

AU - Denovan-Wright, Eileen M.

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AU - Cascio, Maria G.

AU - Pertwee, Roger G.

AU - Thakur, Ganesh A.

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N2 - 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.

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

Abstract

Bibliographical note

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