title: Novel adamantyl cannabinoids as CB1 receptor probes.
abstract: In previous studies, compound 1 (AM411), a 3-(1-adamantyl) analogue of the phytocannabinoid (-)-Δ(8)-tetrahydrocannabinol (Δ(8)-THC), was shown to have improved affinity and selectivity for the CB1 receptor. In this work, we further explored the role of the 1-adamantyl group at the C-3 position in a series of tricyclic cannabinoid analogues modified at the 9-northern aliphatic hydroxyl (NAH) position. Of these, 9-hydroxymethyl hexahydrocannabinol 11 (AM4054) exhibited high CB1 affinity and full agonist profile. In the cAMP assay, the 9-hydroxymethyl cannabinol analogue 24 (AM4089) had a partial agonist profile, with high affinity and moderate selectivity for rCB1 over hCB2. In vivo results in rat models of hypothermia and analgesia were congruent with in vitro data. Our in vivo data indicate that 3-(1-adamantyl) substitution, within NAH cannabinergics, imparts improved pharmacological profiles when compared to the corresponding, traditionally used 3-dimethylheptyl analogues and identifies 11 and 24 as potentially useful in vivo CB1 cannabinergic probes.
authors.affiliation: Center for Drug Discovery, Northeastern University , 116 Mugar Hall, 360 Huntington Avenue, Boston, Massachusetts 02115, USA. g.thakur@neu.edu
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Shama
authors.initials: S
authors.lastname: Bajaj
authors.forename: Carol
authors.initials: C
authors.lastname: Paronis
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.forename: Anna L
authors.initials: AL
authors.lastname: Bowman
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Barak
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Demon
authors.initials: D
authors.lastname: Parrish
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis* / Q000494:pharmacology*; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D019393:Arrestin / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis*; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007035:Hypothermia / Q000139:chemically induced; D008958:Models, Molecular; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D019393:Arrestin; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP; D000218:Adamantane