nad a22 4500 555222551 20190203201236.0 cr unu---uuuuu 190203e201810 xx s 000 0 eng 10.5167/uzh-165836 doi 10.1126/sciadv.aav1966 doi (ZORA)oai:www.zora.uzh.ch:165836 570 ddc 30402545 pmid High-throughput screening for selective appetite modulators: a multibehavioral and translational drug discovery strategy [Elektronische Daten] [Josua Jordi, Drago Guggiana-Nilo, Andrew D Bolton, Srishti Prabha, Kaitlyn Ballotti, Kristian Herrera, Andrew J Rennekamp, Randall T Peterson, Thomas A Lutz, Florian Engert] openAccess eu-repo 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. Institute of Veterinary Physiology zora Jordi Josua joint author Guggiana-Nilo Drago joint author Bolton Andrew D. joint author Prabha Srishti joint author Ballotti Kaitlyn joint author Herrera Kristian joint author Rennekamp Andrew J. joint author Peterson Randall T. joint author Lutz Thomas A. joint author Engert Florian joint author Science Advances 4(10):eaav1966 https://www.zora.uzh.ch/id/eprint/165836/1/Jordi_Science_Advanced_2018.pdf text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora ZORA 856 40 https://www.zora.uzh.ch/id/eprint/165836/1/Jordi_Science_Advanced_2018.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Jordi Josua joint author ZORA 700 1- Guggiana-Nilo Drago joint author ZORA 700 1- Bolton Andrew D. joint author ZORA 700 1- Prabha Srishti joint author ZORA 700 1- Ballotti Kaitlyn joint author ZORA 700 1- Herrera Kristian joint author ZORA 700 1- Rennekamp Andrew J. joint author ZORA 700 1- Peterson Randall T. joint author ZORA 700 1- Lutz Thomas A. joint author ZORA 700 1- Engert Florian joint author ZORA 773 0- Science Advances 4(10):eaav1966 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article openAccess