Improved cyclobutyl nabilone analogs as potent CB1 receptor agonists

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 c...

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Vydáno v:European journal of medicinal chemistry Ročník 230; s. 114027 - 114037
Hlavní autoři: Papanastasiou, Ioannis P., Georgiadis, Markos-Orestis, Iliopoulos-Tsoutsouvas, Christos, Paronis, Carol A., Brust, Christina A., Tran, Ngan K., Ji, Lipin, Ma, Xiaoyu, Wood, JodiAnne T., Zvonok, Nikolai, Tong, Fei, Bohn, Laura M., Nikas, Spyros P., Makriyannis, Alexandros
Médium: Journal Article
Jazyk:angličtina
Vydáno: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2022
Elsevier
Témata:
Cannabinoids
CB1 receptor
Chemistry, Medicinal
Dronabinol - analogs & derivatives
Dronabinol - pharmacology
Life Sciences & Biomedicine
Nabilone analogs
Pharmacology & Pharmacy
Receptor, Cannabinoid, CB1 - agonists
SAR studies
Science & Technology
Structure-Activity Relationship
SAR studies
Cannabinoids
Nabilone analogs
CB1 receptor
AM2389
SIDE-CHAIN
LIGAND
ISSN:0223-5234, 1768-3254, 1768-3254
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Shrnutí: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. [Display omitted] •We explored the C3 side-chain in the hexahydrocannabinol template in terms of chain length and terminal substitution.•The cyclobutyl nabilone analog AM8936 with C6′ cyano-substitution was the most successful.•AM8936 behaved as a balanced and potent CB1 agonist in functional assays.•AM8936 behaved as a potent CB1 agonist in vivo.•Our structure activity relationships are highlighted via docking on the hCB1 crystal structure.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2021.114027