Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential

Reem Smoum; Christeene Haj; Shira Hirsch; Alina Nemirovski; Zhannah Yekhtin; Benny Bogoslavsky; Gaganjyot Kaur Bakshi; Mukesh Chourasia; Ruth Gallily; Joseph Tam; Raphael Mechoulam

doi:10.3390/molecules27041382

Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential

Molecules. 2022 Feb 18;27(4):1382. doi: 10.3390/molecules27041382.

Affiliations

¹ The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
² The Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
³ The Laboratory for Molecular Structure Analysis, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
⁴ Center for Computational Biology and Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida 201301, India.

Abstract

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (K_i = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [³⁵S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC₅₀ = 2.59 nM, E_(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.

Keywords: cannabinoid agonists; fenchone; hCB2 receptor; inflammation.

MeSH terms

Camphanes / chemical synthesis
Camphanes / chemistry*
Camphanes / pharmacology*
Cannabinoid Receptor Agonists / chemical synthesis
Cannabinoid Receptor Agonists / chemistry*
Cannabinoid Receptor Agonists / pharmacology*
Chemistry Techniques, Synthetic
Dose-Response Relationship, Drug
Drug Design*
Humans
Ligands
Models, Molecular
Molecular Structure
Norbornanes / chemical synthesis
Norbornanes / chemistry*
Norbornanes / pharmacology*
Protein Binding
Receptor, Cannabinoid, CB2 / agonists
Receptor, Cannabinoid, CB2 / chemistry*
Spectrum Analysis
Structure-Activity Relationship

Substances

Camphanes
Cannabinoid Receptor Agonists
Ligands
Norbornanes
Receptor, Cannabinoid, CB2
fenchone