3'-functionalized adamantyl cannabinoid receptor probes

Journal of Medicinal Chemistry
Go OgawaAlexandros Makriyannis

Abstract

The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids, and we have previously shown that this chain could be substituted successfully by adamantyl or other polycyclic groups. In an effort to explore the pharmacophoric features of these conformationally fixed groups, we have synthesized a series of analogues in which the C3 position is substituted directly with an adamantyl group bearing functionality at one of the tertiary carbon atoms. These substituents included the electrophilic isothiocyanate and photoactivatable azido groups, both of which are capable of covalent attachment with the target protein. Our results show that substitution at the 3'-adamantyl position can lead to ligands with improved affinities and CB1/CB2 selectivities. Our work has also led to the development of two successful covalent probes with high affinities for both cannabinoid receptors, namely, the electrophilic isothiocyanate AM994 and the photoactivatable aliphatic azido AM993 analogues.

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Apr 30, 2013·Journal of Medicinal Chemistry·Ganesh A ThakurAlexandros Makriyannis
Nov 30, 2013·Journal of Medicinal Chemistry·Rishi SharmaAlexandros Makriyannis

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Citations

Jul 6, 2017·The Journal of Organic Chemistry·Thanh C HoAlexandros Makriyannis
Jun 29, 2017·Pharmacological Reviews·Anna CooperAndrea J Vernall
Nov 28, 2019·International Journal of Molecular Sciences·Szymon HryhorowiczRyszard Słomski
Dec 5, 2016·Purinergic Signalling·Xue YangAd P IJzerman
Oct 5, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shakiru O AlapafujaAlexandros Makriyannis
Feb 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yingpeng LiuAlexandros Makriyannis
Jul 7, 2020·IScience·Fred ShahbaziJohn F Trant
Feb 27, 2021·Bioorganic & Medicinal Chemistry Letters·Thanh C HoAlexandros Makriyannis
Mar 25, 2021·Journal of Medicinal Chemistry·Shan JiangAlexandros Makriyannis
Jul 2, 2016·Journal of Medicinal Chemistry·Shashank KulkarniAlexandros Makriyannis
Feb 9, 2018·Journal of the American Chemical Society·Marjolein SoethoudtMario van der Stelt

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