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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

Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Playa Ancha, Valparaíso 2360102, Chile
Laboratorio de Bionanotecnología, Universidad Bernardo OHiggins, General Gana 1702, Santiago 8320000, Chile
Departamento de Química, Universidad Técnico Federico Santa María, Av. España 1680, Valparaíso 2390123, Chile
Facultad de Farmacia, Universidad de Valparaíso, Av Gran Bretaña 1091, Valparaíso 2360102, Chile
Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Lira 85, 5th Floor, Santiago 8330074, Chile
Facultad de Ciencia, Universidad San Sebastián, Campus Los Leones, Santiago 7510157, Chile
Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andrés Bello, Quillota 980, Viña del Mar 2531015, Chile
Pharmacy Department, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago 702843, Chile
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Molecules 2017, 22(3), 404;
Received: 27 January 2017 / Revised: 28 February 2017 / Accepted: 2 March 2017 / Published: 5 March 2017
(This article belongs to the Section Medicinal Chemistry)
PDF [12860 KB, uploaded 7 March 2017]


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. View Full-Text
Keywords: QSAR; CoMSIA; beta-3 adrenergic receptor; diabetes; obesity; mirabegron; vibegron; indole QSAR; CoMSIA; beta-3 adrenergic receptor; diabetes; obesity; mirabegron; vibegron; indole

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Apablaza, G.; Montoya, L.; Morales-Verdejo, C.; Mellado, M.; Cuellar, M.; Lagos, C.F.; Soto-Delgado, J.; Chung, H.; Pessoa-Mahana, C.D.; Mella, J. 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. Molecules 2017, 22, 404.

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