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  3. N-adamantyl-anthranil amide derivatives: New selective ligands for the cannabinoid receptor subtype 2 (CB2R)

N-adamantyl-anthranil amide derivatives: New selective ligands for the cannabinoid receptor subtype 2 (CB2R)

  • Eur J Med Chem. 2023 Feb 15;248:115109. doi: 10.1016/j.ejmech.2023.115109.
Giovanni Graziano 1,  Pietro Delre 2,  Francesca Carofiglio 1,  Josè Brea 3,  Alessia Ligresti 4,  Magdalena Kostrzewa 4,  Chiara Riganti 5,  Claudia Gioè-Gallo 6,  Maria Majellaro 6,  Orazio Nicolotti 1,  Nicola Antonio Colabufo 1,  Carmen Abate 7,  Maria Isabel Loza 3,  Eddy Sotelo 6,  Giuseppe Felice Mangiatordi 2,  Marialessandra Contino 8,  Angela Stefanachi 9,  Francesco Leonetti 1
Affiliations

Affiliations

  • 1 Department of Pharmacy-Pharmaceutical Sciences, University of the Studies of Bari "Aldo Moro", Via E.Orabona 4, 70125, Bari, Italy.
  • 2 CNR - Institute of Crystallography, Via Giovanni Amendola, 122/O, 70126, Bari, Italy.
  • 3 Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Av. Barcelona, 15782, Santiago de Compostela, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • 4 Institute of Biomolecular Chemistry, National Research Council of Italy, Via Campi Flegrei 34, 80078, Pozzuoli, NA, Italy.
  • 5 Department of Oncology, University of Turin, Turin, Italy.
  • 6 Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela, 15782, Spain.
  • 7 Department of Pharmacy-Pharmaceutical Sciences, University of the Studies of Bari "Aldo Moro", Via E.Orabona 4, 70125, Bari, Italy; CNR - Institute of Crystallography, Via Giovanni Amendola, 122/O, 70126, Bari, Italy.
  • 8 Department of Pharmacy-Pharmaceutical Sciences, University of the Studies of Bari "Aldo Moro", Via E.Orabona 4, 70125, Bari, Italy. Electronic address: marialessandra.contino@uniba.it.
  • 9 Department of Pharmacy-Pharmaceutical Sciences, University of the Studies of Bari "Aldo Moro", Via E.Orabona 4, 70125, Bari, Italy. Electronic address: angela.stefanachi@uniba.it.
PMID: 36657299 DOI: 10.1016/j.ejmech.2023.115109
Abstract

Cannabinoid type 2 receptor (CB2R) is a G-protein-coupled receptor that, together with Cannabinoid type 1 receptor (CB1R), endogenous cannabinoids and Enzymes responsible for their synthesis and degradation, forms the EndoCannabinoid System (ECS). In the last decade, several studies have shown that CB2R is overexpressed in activated central nervous system (CNS) microglia cells, in disorders based on an inflammatory state, such as neurodegenerative diseases, neuropathic pain, and Cancer. For this reason, the anti-inflammatory and immune-modulatory potentials of CB2R ligands are emerging as a novel therapeutic approach. The design of selective ligands is however hampered by the high sequence homology of transmembrane domains of CB1R and CB2R. Based on a recent three-arm pharmacophore hypothesis and latest CB2R crystal structures, we designed, synthesized, and evaluated a series of new N-adamantyl-anthranil amide derivatives as CB2R selective ligands. Interestingly, this new class of compounds displayed a high affinity for human CB2R along with an excellent selectivity respect to CB1R. In this respect, compounds exhibiting the best pharmacodynamic profile in terms of CB2R affinity were also evaluated for the functional behavior and molecular docking simulations provided a sound rationale by highlighting the relevance of the arm 1 substitution to prompt CB2R action. Moreover, the modulation of the pro- and anti-inflammatory cytokines production was also investigated to exert the ability of the best compounds to modulate the inflammatory cascade.

Keywords

Anti-inflammatory; CB2R; CB2R agonism and CB2R antagonism; N-adamantyl-anthranil amide derivatives.

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