title: 3'-functionalized adamantyl cannabinoid receptor probes.
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.
authors.affiliation: †Department of Chemistry, University of Hawaii at Manoa, 2545 The Mall, Honolulu, Hawaii 96822, United States.
authors.forename: Go
authors.initials: G
authors.lastname: Ogawa
authors.affiliation: †Department of Chemistry, University of Hawaii at Manoa, 2545 The Mall, Honolulu, Hawaii 96822, United States.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Tius
authors.affiliation: ‡Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Zhou
authors.affiliation: ‡Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.affiliation: ‡Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
authors.forename: Aneetha
authors.initials: A
authors.lastname: Halikhedkar
authors.affiliation: ‡Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
authors.forename: Srikrishnan
authors.initials: S
authors.lastname: Mallipeddi
authors.affiliation: ‡Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.|§King Abdulaziz University, Jeddah, 22254, Saudi Arabia.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D002186:Cannabinoids / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D015336:Molecular Probe Techniques; D015335:Molecular Probes / Q000737:chemistry* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002186:Cannabinoids; D015335:Molecular Probes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D000218:Adamantane