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

Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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.
DOI: 10.1021/acschemneuro.4c00426
Authors: Matthew N. McCarroll, Elizabeth Sisko, Jung Ho Gong, Jinfeng Teng, Jack Taylor, Douglas Myers-Turnbull, Drew Young, Grant Burley, Lain X. Pierce, Ryan E. Hibbs, David Kokel, Jason K. Sello
Language: English
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Silicon Valley Community Foundation, Paul G. Allen Family Foundation, Chan Zuckerberg Initiative, National Institutes of Health, University of California, San Diego, University of California, San Francisco, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Weill Institute for Neurosciences, University of California, San Francisco, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Intramural Research Program
Awards: Studies of the antibacterial activity of and resistance to molecules targeting the ClpP peptidase, G2090380553, G2721085853, G3602596493, G7627919280, G790576545, G9000047831, Structure and Function of GABA-A receptors, G975739267
OpenAlex ID: W4402584980
FWCI: 0.785
Cites: 41
Cited by: 5
Related to: 10