title: Indol-3-yl-tetramethylcyclopropyl ketones: effects of indole ring substitution on CB2 cannabinoid receptor activity.
abstract: A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB 2 cannabinoid receptor ligands. Two unsubstituted indoles ( 5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB 2 and CB 1 binding affinities and activity in a CB 2 in vitro functional assay. Indole ring substitutions had varying effects on CB 2 and CB 1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB 2/CB 1 binding selectivity in some cases (i.e., 7- 9, 15- 20). All indoles with the morpholino-ethyl side chain ( 32- 43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs ( 5- 31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia ( 32, 15).
authors.affiliation: Neurological Diseases Research, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. jennifer.frost@abbott.com
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Frost
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dart
authors.forename: Karin R
authors.initials: KR
authors.lastname: Tietje
authors.forename: Tiffany R
authors.initials: TR
authors.lastname: Garrison
authors.forename: George K
authors.initials: GK
authors.lastname: Grayson
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Daza
authors.forename: Odile F
authors.initials: OF
authors.lastname: El-Kouhen
authors.forename: Loan N
authors.initials: LN
authors.lastname: Miller
authors.forename: Lanlan
authors.initials: L
authors.lastname: Li
authors.forename: Betty B
authors.initials: BB
authors.lastname: Yao
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008968:Molecular Conformation; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D007659:Ketones; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2