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

Authors :
Reem Smoum
Christeene Haj
Shira Hirsch
Alina Nemirovski
Zhannah Yekhtin
Benny Bogoslavsky
Gaganjyot Kaur Bakshi
Mukesh Chourasia
Ruth Gallily
Joseph Tam
Raphael Mechoulam
Source :
Molecules, Vol 27, Iss 4, p 1382 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

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 (Ki = 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.

Details

Language :
English
ISSN :
14203049
Volume :
27
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.9049d27258a6472f873e103257af4539
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules27041382