title: Design, synthesis, biological evaluation and binding mode modeling of benzimidazole derivatives targeting the cannabinoid receptor type 1.
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.
authors: Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Catolica de Chile, Santiago, Chile.
authors: Christian
authors: C
authors: Espinosa-Bustos
authors: Carlos F
authors: CF
authors: Lagos
authors: Javier
authors: J
authors: Romero-Parra
authors: Ana M
authors: AM
authors: Zárate
authors: Jaime
authors: J
authors: Mella-Raipán
authors: Hernán
authors: H
authors: Pessoa-Mahana
authors: Gonzalo
authors: G
authors: Recabarren-Gajardo
authors: Patricio
authors: P
authors: Iturriaga-Vásquez
authors: Ricardo A
authors: RA
authors: Tapia
authors: C David
authors: CD
authors: Pessoa-Mahana
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D017076:Computer-Aided Design; D003511:Cyclohexanols / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; C571130:CNR1 protein, human; D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C031000:benzimidazole
keywords: Benzimidazole derivatives; Binding affinity; Cannabinoid receptor type 1; CoMFA; Molecular modeling