Indol-3-yl-tetramethylcyclopropyl Ketones: Effects of Indole Ring Substitution on CB2 Cannabinoid Receptor Activity

• Published in: Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1904-1912
• Main Authors: Frost, Jennifer M, Dart, Michael J, Tietje, Karin R, Garrison, Tiffany R, Grayson, George K, Daza, Anthony V, El-Kouhen, Odile F, Miller, Loan N, Li, Lanlan, Yao, Betty B, Hsieh, Gin C, Pai, Madhavi, Zhu, Chang Z, Chandran, Prasant, Meyer, Michael D
• Format: Article
• Language: English
• Subjects: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Binding, Competitive; Biological and medical sciences; Cell Line; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Ligands; Medical sciences; Miscellaneous; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Receptor, Cannabinoid, CB1 - drug effects; Receptor, Cannabinoid, CB2 - drug effects; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm7011613

A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB2 cannabinoid receptor ligands. Two unsubstituted indoles (5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB2 and CB1 binding affinities and activity in a CB2 in vitro functional assay. Indole ring substitutions had varying effects on CB2 and CB1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB2/CB1 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).