title: Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity.
abstract: Several 3-acylindoles with high affinity for the CB(2) cannabinoid receptor and selectivity over the CB(1) receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB(2) agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB(2) receptor. A study of N1 nonaromatic side chain variants provided potent agonists at the CB(2) receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB(2) receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB(2) receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB(2) functional assay than were nonaromatic side chain analogues.
authors.affiliation: Neurological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47W, AP9A, 100 Abbott Park Road, Abbott Park, Illinois 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: 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: D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D007659:Ketones; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2