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, 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).