title: Combined CoMFA and CoMSIA 3D-QSAR study of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.
abstract: The preceding years have brought an exponential increase in our understanding of the endocannabinoid system (ECS), including the knowledge of CB1 and CB2 cannabinoid receptors, endocannabinoids, and the enzymes that synthesize and degrade endocannabinoids. Among these ECS components CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential to treat numerous pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. Recently, our research group has reported a new series of non-cytotoxic benzo[d]imidazoles and benzo[b]thiophenes displaying high CB2/CB1 selectivity index. In order to investigate the structural requirements for CB2 ligands and to derive a predictive model that can be used for the design of novel selective CB2 ligands, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The CoMFA and CoMSIA models displayed high external predictability (rpred20.919 and 0.908) and good statistical robustness. Valuable information regarding the steric, electrostatic and hydrophobic properties of the molecules was obtained, and several modifications around both heterocycles were evaluated with the aim to generate new promising series of benzo[d]imidazoles and benzo[b]thiophenes derivatives displaying high CB2 selectivity and low toxicity.
authors.affiliation: Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago, Chile.
authors.forename: Javier
authors.initials: J
authors.lastname: Romero-Parra
authors.affiliation: Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago, Chile.
authors.forename: Hery
authors.initials: H
authors.lastname: Chung
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, 702843, Santiago, Chile.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Tapia
authors.affiliation: Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Faúndez
authors.affiliation: Universidad Bernardo OHiggins, Laboratorio de Bionanotecnología, General Gana 1702, Santiago, Chile.
authors.forename: Cesar
authors.initials: C
authors.lastname: Morales-Verdejo
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso, Casilla 5030, Chile.
authors.forename: Marcos
authors.initials: M
authors.lastname: Lorca
authors.affiliation: Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago Centro 8330074, Santiago, Chile; Facultad de Ciencia, Universidad San Sebastián, Campus Los Leones, Lota 2465, Providencia 7510157, Santiago, Chile.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.affiliation: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago, Chile.
authors.forename: C
authors.initials: C
authors.lastname: David Pessoa-Mahana
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso, Casilla 5030, Chile. Electronic address: jaime.mella@uv.cl.
authors.forename: Jaime
authors.initials: J
authors.lastname: Mella
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry*; D002186:Cannabinoids / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry*; D055672:Static Electricity; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D001562:Benzimidazoles; D002186:Cannabinoids; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013876:Thiophenes; C088015:benzothiophene; C031000:benzimidazole
keywords: 3D-QSAR; Benzimidazole; Benzothiophene; CB2 cannabinoids; CoMFA; CoMSIA