TY - JOUR
T1 - Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands
T2 - from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands
AU - Gado, Francesca
AU - Ferrisi, Rebecca
AU - Polini, Beatrice
AU - Mohamed, Kawthar A.
AU - Ricardi, Caterina
AU - Lucarini, Elena
AU - Carpi, Sara
AU - Domenichini, Federica
AU - Stevenson, Lesley A.
AU - Rapposelli, Simona
AU - Saccomanni, Giuseppe
AU - Nieri, Paola
AU - Ortore, Gabriella
AU - Pertwee, Roger G.
AU - Ghelardini, Carla
AU - Di Cesare Mannelli, Lorenzo
AU - Chiellini, Grazia
AU - Laprairie, Robert B.
AU - Manera, Clementina
PY - 2022/7/28
Y1 - 2022/7/28
N2 - The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand FD-22a displayed anti-inflammatory activity in a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Finally, computational studies clarified the binding mode of these compounds inside the CB2R, further confirming their bitopic nature.
AB - The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand FD-22a displayed anti-inflammatory activity in a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Finally, computational studies clarified the binding mode of these compounds inside the CB2R, further confirming their bitopic nature.
UR - http://www.scopus.com/inward/record.url?scp=85135373007&partnerID=8YFLogxK
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U2 - 10.1021/acs.jmedchem.2c00582
DO - 10.1021/acs.jmedchem.2c00582
M3 - Article
C2 - 35849804
AN - SCOPUS:85135373007
SN - 0022-2623
VL - 65
SP - 9918
EP - 9938
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -