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 | |
| Publication status | Published - 14 Jan 2016 |
Cite this
Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s). / Kulkarni, Pushkar M.; Kulkarni, Abhijit R.; Korde, Anisha; Tichkule, Ritesh B.; Laprairie, Robert B.; Denovan-Wright, Eileen M.; Zhou, Han; Janero, David R.; Zvonok, Nikolai; Makriyannis, Alexandros; Cascio, Maria G.; Pertwee, Roger G.; Thakur, Ganesh A.
In: Journal of Medicinal Chemistry, Vol. 59, No. 1, 14.01.2016, p. 44-60.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)
AU - Kulkarni, Pushkar M.
AU - Kulkarni, Abhijit R.
AU - Korde, Anisha
AU - Tichkule, Ritesh B.
AU - Laprairie, Robert B.
AU - Denovan-Wright, Eileen M.
AU - Zhou, Han
AU - Janero, David R.
AU - Zvonok, Nikolai
AU - Makriyannis, Alexandros
AU - Cascio, Maria G.
AU - Pertwee, Roger G.
AU - Thakur, Ganesh A.
N1 - 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.
PY - 2016/1/14
Y1 - 2016/1/14
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.
AB - 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.
U2 - 10.1021/acs.jmedchem.5b01303
DO - 10.1021/acs.jmedchem.5b01303
M3 - Article
VL - 59
SP - 44
EP - 60
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -