2. Academic Validation
  3. Development of N-(1-Adamantyl)benzamides as Novel Anti-Inflammatory Multitarget Agents Acting as Dual Modulators of the Cannabinoid CB2 Receptor and Fatty Acid Amide Hydrolase

Development of N-(1-Adamantyl)benzamides as Novel Anti-Inflammatory Multitarget Agents Acting as Dual Modulators of the Cannabinoid CB2 Receptor and Fatty Acid Amide Hydrolase

  • J Med Chem. 2023 Jan 12;66(1):235-250. doi: 10.1021/acs.jmedchem.2c01084.
Francesca Intranuovo 1,  Leonardo Brunetti 1,  Pietro DelRe 2,  Giuseppe Felice Mangiatordi 2,  Angela Stefanachi 1,  Antonio Laghezza 1,  Mauro Niso 1,  Francesco Leonetti 1,  Fulvio Loiodice 1,  Alessia Ligresti 3,  Magdalena Kostrzewa 3,  Jose Brea 4 5,  Maria Isabel Loza 4 5,  Eddy Sotelo 6,  Michele Saviano 7,  Nicola Antonio Colabufo 1,  Chiara Riganti 8,  Carmen Abate 1 2,  Marialessandra Contino 1
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia-Scienze Del Farmaco, Università Degli Studi di Bari ALDO MORO, Via Orabona 4, Bari 70125, Italy.
  • 2 Institute of Crystallography, National Research Council of Italy, Via Amendola, 122/o, Bari 70126, Italy.
  • 3 Institute of Biomolecular Chemistry, National Research Council of Italy, Via Campi Flegrei 34, Pozzuoli 80078, Italy.
  • 4 Innopharma Screening Platform, BioFarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 5 Department of Pharmacology, Pharmacy and Pharmaceutical Technology. School of Pharmacy, University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 6 ComBioMed Research Group, Centro de Química Biológica y Materiales Moleculares (CIQUS), University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 7 Institute of Crystallography, National Research Council of Italy, Via Vivaldi, 43, Caserta 81100, Italy.
  • 8 Dipartimento di Oncologia, Università Degli Studi di Torino, Torino 10126, Italy.
PMID: 36542836 DOI: 10.1021/acs.jmedchem.2c01084
Abstract

Cannabinoid type 2 receptor (CB2R), belonging to the endocannabinoid system, is overexpressed in pathologies characterized by inflammation, and its activation counteracts inflammatory states. Fatty acid amide hydrolase (FAAH) is an Enzyme responsible for the degradation of the main endocannabinoid anandamide; thus, the simultaneous CB2R activation and FAAH inhibition may be a synergistic anti-inflammatory strategy. Encouraged by principal component analysis (PCA) data identifying a wide chemical space shared by CB2R and FAAH ligands, we designed a small library of adamantyl-benzamides, as potential dual agents, CB2R agonists, and FAAH inhibitors. The new compounds were tested for their CB2R affinity/selectivity and CB2R and FAAH activity. Derivatives 13, 26, and 27, displaying the best pharmacodynamic profile as CB2R full agonists and FAAH inhibitors, decreased pro-inflammatory and increased anti-inflammatory cytokines production. Molecular docking simulations complemented the experimental findings by providing a molecular rationale behind the observed activities. These multitarget ligands constitute promising anti-inflammatory agents.

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