Design, synthesis, biological evaluation and binding mode modeling of benzimidazole derivatives targeting the cannabinoid receptor type 1

Arch Pharm (Weinheim). 2015 Feb;348(2):81-8. doi: 10.1002/ardp.201400201. Epub 2015 Jan 13.

Abstract

A series of N-acyl-2,5-dimethoxyphenyl-1H-benzimidazoles were designed based on a CoMFA model for cannabinoid receptor type 1 (CB1) ligands. Compounds were synthesized and radioligand binding affinity assays were performed. Eight novel benzimidazoles exhibited affinity for the CB1 receptor in the nanomolar range, and the most promising derivative compound 5 displayed a K(i) value of 1.2 nM when compared to CP55,940. These results confirm our previously reported QSAR model on benzimidazole derivatives, providing new information for the development of small molecules with high CB1 affinity.

Keywords: Benzimidazole derivatives; Binding affinity; Cannabinoid receptor type 1; CoMFA; Molecular modeling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / metabolism*
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Cannabinoid Receptor Agonists / chemical synthesis*
  • Cannabinoid Receptor Agonists / metabolism*
  • Cannabinoid Receptor Agonists / pharmacology
  • Computer-Aided Design
  • Cyclohexanols / metabolism
  • Drug Design*
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Quantitative Structure-Activity Relationship
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / chemistry
  • Receptor, Cannabinoid, CB1 / metabolism*

Substances

  • Benzimidazoles
  • CNR1 protein, human
  • Cannabinoid Receptor Agonists
  • Cyclohexanols
  • Ligands
  • Receptor, Cannabinoid, CB1
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • benzimidazole