Abstract
Synthetic indole cannabinoids characterized by a 2',2'-dimethylindan-5'-oyl group at the indole C3 position constitute a new class of ligands possessing high affinity for human CB(2) receptors at a nanomolar concentration and a good selectivity index. Starting from the neutral antagonist 4, the effects of indole core modification on the pharmacodynamic profile of the ligands were investigated. Several N1 side chains afforded potent and CB(2)-selective neutral antagonists, notably derivatives 26 (R(1) = n-propyl, R(2) = H) and 35 (R(1) = 4-pentynyl, R(2) = H). Addition of a methyl group at C2 improved the selectivity for the CB(2) receptor. Moreover, C2 indole substitution may control the CB(2) activity as shown by the functionality switch in 35 (antagonist) and 49 (R(1) = 4-pentynyl, R(2) = CH(3), partial agonist).