title: 2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β₃-Adrenergic Activity.
abstract: The β₃ adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β₃ adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β₃ adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β₃ adrenergic activity is given.
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile. apablaza.gaston@gmail.com.
authors.forename: Gastón
authors.initials: G
authors.lastname: Apablaza
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile. luisa.montoya.lara@gmail.com.
authors.forename: Luisa
authors.initials: L
authors.lastname: Montoya
authors.affiliation: Laboratorio de Bionanotecnología, Universidad Bernardo OHiggins, General Gana 1702, Santiago 8320000, Chile. camoralv@uc.cl.
authors.forename: Cesar
authors.initials: C
authors.lastname: Morales-Verdejo
authors.affiliation: Departamento de Química, Universidad Técnico Federico Santa María, Av. España 1680, Valparaíso 2390123, Chile. marco.mellado@postgrado.usm.cl.|Facultad de Farmacia, Universidad de Valparaíso, Av Gran Bretaña 1091, Valparaíso 2360102, Chile. marco.mellado@postgrado.usm.cl.
authors.forename: Marco
authors.initials: M
authors.lastname: Mellado
authors.affiliation: Facultad de Farmacia, Universidad de Valparaíso, Av Gran Bretaña 1091, Valparaíso 2360102, Chile. mauricio.cuellar@uv.cl.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cuellar
authors.affiliation: Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, Chile. cflagos@uc.cl.|Facultad de Ciencia, Universidad San Sebastián, Campus Los Leones, Santiago 7510157, Chile. cflagos@uc.cl.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Lagos
authors.affiliation: Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andrés Bello, Quillota 980, Viña del Mar 2531015, Chile. jorge.soto@unab.cl.
authors.forename: Jorge
authors.initials: J
authors.lastname: Soto-Delgado
authors.affiliation: Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago 702843, Chile. chung.hery@gmail.com.
authors.forename: Hery
authors.initials: H
authors.lastname: Chung
authors.affiliation: Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago 702843, Chile. cpessoa@uc.cl.
authors.forename: Carlos David
authors.initials: CD
authors.lastname: Pessoa-Mahana
authors.affiliation: Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile. jaime.mella@uv.cl.
authors.forename: Jaime
authors.initials: J
authors.lastname: Mella
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D007211:Indoles; D008024:Ligands; C030374:indole
keywords: CoMSIA; QSAR; beta-3 adrenergic receptor; diabetes; indole; mirabegron; obesity; vibegron