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

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• 作者：Jennifer M. Frost ; Michael J. Dart ; Karin R. Tietje ; Tiffany R. Garrison ; George K. Grayson ; Anthony V. Daza ; Odile F. El-Kouhen ; Loan N. Miller ; Lanlan Li ; Betty B. Yao ; Gin C. Hsieh ; Madhavi Pai ; Ch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1904 - 1912
• 全文大小：150K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

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).