Open AccessSynthesis, Molecular Pharmacology, and Structure–Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists
Author(s) -
Harvey F. Fulo,
Amal Shoeib,
Christian V. Cabanlong,
Alexander H. Williams,
ChangGuo Zhan,
Paul L. Prather,
Gregory B. Dudley
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00442
Subject(s) - chemistry , indole test , cannabinoid , antagonist , stereochemistry , agonist , selectivity , cannabinoid receptor type 2 , cannabinoid receptor , partial agonist , receptor , chemical synthesis , structure–activity relationship , pharmacology , in vitro , biochemistry , medicine , catalysis
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).