Indol-3-yl-tetramethylcyclopropyl ketones: effects of indole ring substitution on CB2 cannabinoid receptor activity.
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).
Frost
Jennifer M
JM
Neurological Diseases Research, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. jennifer.frost@abbott.com
Dart
Michael J
MJ
Tietje
Karin R
KR
Garrison
Tiffany R
TR
Grayson
George K
GK
Daza
Anthony V
AV
El-Kouhen
Odile F
OF
Miller
Loan N
LN
Li
Lanlan
L
Yao
Betty B
BB
Hsieh
Gin C
GC
Pai
Madhavi
M
Zhu
Chang Z
CZ
Chandran
Prasant
P
Meyer
Michael D
MD
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D007659:Ketones; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2