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

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 CB₂ 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 CB₂-selective neutral antagonists, notably derivatives 26 (R¹ = n-propyl, R² = H) and 35 (R¹ = 4-pentynyl, R² = H). Addition of a methyl group at C2 improved the selectivity for the CB₂ receptor. Moreover, C2 indole substitution may control the CB₂ activity as shown by the functionality switch in 35 (antagonist) and 49 (R¹ = 4-pentynyl, R² = CH₃, partial agonist).

SUBMITTER: Fulo HF 

PROVIDER: S-EPMC8683641 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature