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Molecular Pharmacology

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Research ArticleArticle

Detection of New Biased Agonists for the Serotonin 5-HT2A Receptor: Modeling and Experimental Validation

Maria Martí-Solano, Alba Iglesias, Gianni de Fabritiis, Ferran Sanz, José Brea, M. Isabel Loza, Manuel Pastor and Jana Selent
Molecular Pharmacology April 2015, 87 (4) 740-746; DOI: https://doi.org/10.1124/mol.114.097022
Maria Martí-Solano
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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Alba Iglesias
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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Gianni de Fabritiis
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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Ferran Sanz
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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José Brea
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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M. Isabel Loza
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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Manuel Pastor
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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Jana Selent
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain (M.M.-S., G.F., F.S., M.P., J.S.), and Department of Pharmacology, Institute of Industrial Pharmacy, Faculty of Pharmacy, Santiago de Compostela University, Santiago de Compostela, Spain (A.I., J.B., M.I.L.)
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Abstract

Detection of biased agonists for the serotonin 5-HT2A receptor can guide the discovery of safer and more efficient antipsychotic drugs. However, the rational design of such drugs has been hampered by the difficulty detecting the impact of small structural changes on signaling bias. To overcome these difficulties, we characterized the dynamics of ligand-receptor interactions of known biased and balanced agonists using molecular dynamics simulations. Our analysis revealed that interactions with residues S5.46 and N6.55 discriminate compounds with different functional selectivity. Based on our computational predictions, we selected three derivatives of the natural balanced ligand serotonin and experimentally validated their ability to act as biased agonists. Remarkably, our approach yielded compounds promoting an unprecedented level of signaling bias at the 5-HT2A receptor, which could help interrogate the importance of particular pathways in conditions like schizophrenia.

Footnotes

    • Received December 2, 2014.
    • Accepted February 6, 2015.
  • This work was funded by the Ministerio de Educación y Ciencia [Grants SAF2009-13609-C04-04 and SAF2009-13609-C04-01] and La MARATÓ de TV3 Foundation [Grant 091010]. M.M.-S. is supported by a doctoral fellowship from the University and Research Secretariat of the Catalan Government and the European Social Fund [2014FI_B2 00143]. J.S. acknowledges support from the Instituto de Salud Carlos III El Fondo Europeo de Desarrollo Regional (FEDER) [CP12/03139] and the GPCR-Ligand Interactions, Structures, and Transmembrane Signalling (GLISTEN) European Research Network. A.I. is supported by a Formación de Personal Investigador (FPI) grant from the Spanish Ministry of Economy and Competitiveness.

  • dx.doi.org/10.1124/mol.114.097022.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (4)
Molecular Pharmacology
Vol. 87, Issue 4
1 Apr 2015
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Research ArticleArticle

New Biased Agonists for Serotonin 5-HT2A Receptors

Maria Martí-Solano, Alba Iglesias, Gianni de Fabritiis, Ferran Sanz, José Brea, M. Isabel Loza, Manuel Pastor and Jana Selent
Molecular Pharmacology April 1, 2015, 87 (4) 740-746; DOI: https://doi.org/10.1124/mol.114.097022

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Research ArticleArticle

New Biased Agonists for Serotonin 5-HT2A Receptors

Maria Martí-Solano, Alba Iglesias, Gianni de Fabritiis, Ferran Sanz, José Brea, M. Isabel Loza, Manuel Pastor and Jana Selent
Molecular Pharmacology April 1, 2015, 87 (4) 740-746; DOI: https://doi.org/10.1124/mol.114.097022
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