Design and Development of New Dual Target Agents, Cannabinoid Subtype 2 Receptor (CB2R) Agonists, and Fatty Acid Amide Hydrolase (FAAH) Inhibitors against Neurodegeneration
Abstract As dual modulators of Cannabinoid subtype 2 receptor (CB2R) and fatty acid amide hydrolase (FAAH)an arising therapeutic strategy against diseases based on neuroinflammationwe developed a new series of N-adamantyl-benzamides bearing an anthranilic or salicylic scaffold. Derivatives 18, 22, and 25 emerged as an interesting compromise in terms of CB2R activity, CB2R/CB1R selectivity, and FAAH inhibition. All compounds were potent FAAH inhibitors; 18 and 25 acted as unbiased CB2R agonists with no CB1R affinity, whereas 22 was a CB2R antagonist in the cAMP pathway and partial agonist in β-arrestin-2 recruitment. The three compounds were tested in monocytes and macrophages in resting and activated states and in a human activated microglia model with a potent anti-inflammatory action. These results support the CB2R and FAAH engagement as a promising dual strategy against neuroinflammation providing valuable chemical tools for probing the structural determinants underlying CB2R binding, long residence time, and biased signaling.
Authors
- Laura H. Heitman (ORCID: https://orcid.org/0000-0002-1381-8464)
- Chiara Riganti (ORCID: https://orcid.org/0000-0001-9787-4836)
- Giuseppe Felice Mangiatordi (ORCID: https://orcid.org/0000-0003-4042-2841)
- Mariachiara Mammone (ORCID: https://orcid.org/0009-0008-6283-7312)
- Nicola Antonio Colabufo (ORCID: https://orcid.org/0000-0001-5639-7746)
- Maria Grazia Perrone (ORCID: https://orcid.org/0000-0003-4195-5228)
- Angela Stefanachi (ORCID: https://orcid.org/0000-0002-9430-7972)
- Francesco Leonetti (ORCID: https://orcid.org/0000-0003-2043-7464)
- Antonio Laghezza (ORCID: https://orcid.org/0000-0001-6221-6155)
- Jose Manuel Brea (ORCID: https://orcid.org/0000-0002-5523-1979)
- Daniela Espósito (ORCID: https://orcid.org/0000-0001-8993-2071)
- Giovanni Graziano (ORCID: https://orcid.org/0000-0002-5575-3240)
- Carmen Abate (ORCID: https://orcid.org/0000-0001-9292-884X)
- Marı́a Isabel Loza (ORCID: https://orcid.org/0000-0003-4730-0863)
- Alessia Ligresti (ORCID: https://orcid.org/0000-0003-1787-3900)
- Marialessandra Contino (ORCID: https://orcid.org/0000-0002-0713-3151)
- M. Papadopoulos (ORCID: https://orcid.org/0000-0002-6072-3388)
- Francesco Mastropasqua (ORCID: https://orcid.org/0009-0004-7136-2807)
- Annalisa Fanizzi
- Gabriella Rosanna Musillo
- Cas van der Horst
Institutions
- Leiden University (NL)
- Universidade de Santiago de Compostela (ES)
- National Research Council (IT)
- University of Turin (IT)
- University of Bari Aldo Moro (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c02401
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00