Synthesis, Molecular Pharmacology, and Structure-Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists.

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 receptors at a nanomolar concentration and a good selectivity index. Starting from the neutral antagonist , the effects of indole core modification on the pharmacodynamic profile of the ligands were investigated. Several N1 side chains afforded potent and CB-selective neutral antagonists, notably derivatives (R = -propyl, R = H) and (R = 4-pentynyl, R = H). Addition of a methyl group at C2 improved the selectivity for the CB receptor. Moreover, C2 indole substitution may control the CB activity as shown by the functionality switch in (antagonist) and (R = 4-pentynyl, R = CH, partial agonist).