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

Francesca Gado, Rebecca Ferrisi, Beatrice Polini, Kawthar A. Mohamed, Caterina Ricardi, Elena Lucarini, Sara Carpi, Federica Domenichini, Lesley A. Stevenson, Simona Rapposelli, Giuseppe Saccomanni, Paola Nieri, Gabriella Ortore, Roger G. Pertwee, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Grazia Chiellini, Robert B. Laprairie, Clementina Manera

Résultat de recherche: Articleexamen par les pairs

21 Citations (Scopus)

Résumé

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.

Langue d'origineEnglish
Pages (de-à)9918-9938
Nombre de pages21
JournalJournal of Medicinal Chemistry
Volume65
Numéro de publication14
DOI
Statut de publicationPublished - juill. 28 2022

ASJC Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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