A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules.

Autor: McCarroll MN; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94158, United States., Sisko E; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States., Gong JH; Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States., Teng J; Department of Neurobiology, University of California, San Diego, California 92093, United States., Taylor J; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94158, United States.; UCSF Weill Institute for Neurosciences Memory and Aging Center, University of California, San Francisco, California 94158, United States., Myers-Turnbull D; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94158, United States., Young D; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94158, United States., Burley G; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States., Pierce LX; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States., Hibbs RE; Department of Neurobiology, University of California, San Diego, California 92093, United States., Kokel D; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94158, United States., Sello JK; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
Jazyk: angličtina
Zdroj: ACS chemical neuroscience [ACS Chem Neurosci] 2024 Sep 17. Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1021/acschemneuro.4c00426
Abstrakt: A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABA A potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABA A receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules' nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.
Databáze: MEDLINE
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