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Molecules ; 27(4)2022 Feb 18.
Article in English | MEDLINE | ID: mdl-35209170

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.


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