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 {CB}2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands / F. Gado, R. Ferrisi, B. Polini, K.A. Mohamed, C. Ricardi, E. Lucarini, S. Carpi, F. Domenichini, L.A. Stevenson, S. Rapposelli, G. Saccomanni, P. Nieri, G. Ortore, R.G. Pertwee, C. Ghelardini, L. Di Cesare Mannelli, G. Chiellini, R.B. Laprairie, C. Manera. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:14(2022 Jul 28), pp. 9918-9938. [10.1021/acs.jmedchem.2c00582]
Design, Synthesis, and Biological Activity of New {CB}2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands
F. GadoPrimo
;R. Ferrisi;
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.File | Dimensione | Formato | |
---|---|---|---|
acs.jmedchem.2c00582.pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
4.44 MB
Formato
Adobe PDF
|
4.44 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.