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

Harvey F. Fulo, Amal Shoeib, Christian V. Cabanlong, Alexander H. Williams, Chang Guo Zhan, Paul L. Prather, Gregory B. Dudley

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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).

Original languageEnglish
Pages (from-to)6381-6396
Number of pages16
JournalJournal of Medicinal Chemistry
Volume64
Issue number9
DOIs
StatePublished - May 13 2021

Bibliographical note

Funding Information:
This work was supported in part by the funding from the National Institutes of Health (R01 DA039143) for PLP, with additional support from West Virginia University and the Eberly Family Foundation. Molecular modeling studies were supported by the National Institutes of Health (P20 GM130456 and T32 DA016176).

Publisher Copyright:
© 2021 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Synthesis, Molecular Pharmacology, and Structure-Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists'. Together they form a unique fingerprint.

Cite this