Improved cyclobutyl nabilone analogs as potent CB1 receptor agonists

Ioannis P Papanastasiou; Markos-Orestis Georgiadis; Christos Iliopoulos-Tsoutsouvas; Carol A Paronis; Christina A Brust; Ngan K Tran; Lipin Ji; Xiaoyu Ma; JodiAnne T Wood; Nikolai Zvonok; Fei Tong; Laura M Bohn; Spyros P Nikas; Alexandros Makriyannis

doi:10.1016/j.ejmech.2021.114027

Improved cyclobutyl nabilone analogs as potent CB1 receptor agonists

Eur J Med Chem. 2022 Feb 15:230:114027. doi: 10.1016/j.ejmech.2021.114027. Epub 2021 Dec 27.

Affiliations

¹ Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157-84, Athens, Greece.
² Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157-84, Athens, Greece; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
³ Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
⁴ Skaggs Graduate School of Chemical and Biological Science and Department of Molecular Medicine, Scripps Florida, Jupiter, FL, 33458, USA.
⁵ Department of Molecular Medicine, Scripps Florida, Jupiter, FL, USA.
⁶ Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA; Center for Drug Discovery and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA. Electronic address: a.makriyannis@northeastern.edu.

PMID: 35051750
DOI: 10.1016/j.ejmech.2021.114027

Abstract

In earlier work, we explored the SAR for the C3 side chain pharmacophore in the hexahydrocannabinol template represented by the drug nabilone, which resulted in the development of AM2389. In an effort for further optimization, we have merged features of nabilone and AM2389 and explored the C3 side chain with varying chain lengths and terminal substitutions. Of the compounds described here, a nabilone analog, AM8936, with the C6'-cyano-substituted side chain, was identified as the most successful analog capable of serving as a potential candidate for further development and a valuable tool for further in vivo studies. AM8936 behaved as a balanced and potent CB1 agonist in functional assays and was a potent and efficacious CB1 agonist in vivo. Our SAR studies are highlighted with the docking of AM8936 on the crystal structure of the hCB1 receptor.

Keywords: CB1 receptor; Cannabinoids; Nabilone analogs; SAR studies.

MeSH terms

Dronabinol* / analogs & derivatives
Dronabinol* / pharmacology
Receptor, Cannabinoid, CB1* / agonists
Structure-Activity Relationship

Substances

Receptor, Cannabinoid, CB1
nabilone
Dronabinol