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High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only...

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Autores principales: Jordi, Josua, Guggiana-Nilo, Drago, Bolton, Andrew D, Prabha, Srishti, Ballotti, Kaitlyn, Herrera, Kristian, Rennekamp, Andrew J., Peterson, Randall T., Lutz, Thomas A., Engert, Florian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209392/
https://www.ncbi.nlm.nih.gov/pubmed/30402545
http://dx.doi.org/10.1126/sciadv.aav1966
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author Jordi, Josua
Guggiana-Nilo, Drago
Bolton, Andrew D
Prabha, Srishti
Ballotti, Kaitlyn
Herrera, Kristian
Rennekamp, Andrew J.
Peterson, Randall T.
Lutz, Thomas A.
Engert, Florian
author_facet Jordi, Josua
Guggiana-Nilo, Drago
Bolton, Andrew D
Prabha, Srishti
Ballotti, Kaitlyn
Herrera, Kristian
Rennekamp, Andrew J.
Peterson, Randall T.
Lutz, Thomas A.
Engert, Florian
author_sort Jordi, Josua
collection PubMed
description How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.
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spelling pubmed-62093922018-11-06 High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy Jordi, Josua Guggiana-Nilo, Drago Bolton, Andrew D Prabha, Srishti Ballotti, Kaitlyn Herrera, Kristian Rennekamp, Andrew J. Peterson, Randall T. Lutz, Thomas A. Engert, Florian Sci Adv Research Articles How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species. American Association for the Advancement of Science 2018-10-31 /pmc/articles/PMC6209392/ /pubmed/30402545 http://dx.doi.org/10.1126/sciadv.aav1966 Text en Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Jordi, Josua
Guggiana-Nilo, Drago
Bolton, Andrew D
Prabha, Srishti
Ballotti, Kaitlyn
Herrera, Kristian
Rennekamp, Andrew J.
Peterson, Randall T.
Lutz, Thomas A.
Engert, Florian
High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy
title High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy
title_full High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy
title_fullStr High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy
title_full_unstemmed High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy
title_short High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy
title_sort high-throughput screening for selective appetite modulators: a multibehavioral and translational drug discovery strategy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209392/
https://www.ncbi.nlm.nih.gov/pubmed/30402545
http://dx.doi.org/10.1126/sciadv.aav1966
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