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 beta arrestin2 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.

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: From Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands / Gado F.; Ferrisi R.; Polini B.; Mohamed K.A.; Ricardi C.; Lucarini E.; Carpi S.; Domenichini F.; Stevenson L.A.; Rapposelli S.; Saccomanni G.; Nieri P.; Ortore G.; Pertwee R.G.; Ghelardini C.; Di Cesare Mannelli L.; Chiellini G.; Laprairie R.B.; Manera C.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - ELETTRONICO. - 65:(2022), pp. 9918-9938. [10.1021/acs.jmedchem.2c00582]

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: From Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands

Lucarini E.;Ghelardini C.;Di Cesare Mannelli L.;
2022

Abstract

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 beta arrestin2 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.
2022
65
9918
9938
Gado F.; Ferrisi R.; Polini B.; Mohamed K.A.; Ricardi C.; Lucarini E.; Carpi S.; Domenichini F.; Stevenson L.A.; Rapposelli S.; Saccomanni G.; Nieri P.; Ortore G.; Pertwee R.G.; Ghelardini C.; Di Cesare Mannelli L.; Chiellini G.; Laprairie R.B.; Manera C.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1296002
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