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

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

doi:10.1021/acschemneuro.4c00426

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

ACS Chem Neurosci. 2024 Sep 17. doi: 10.1021/acschemneuro.4c00426. Online ahead of print.

Authors

Matthew N McCarroll^{1

2}, Elizabeth Sisko¹, Jung Ho Gong³, Jinfeng Teng⁴, Jack Taylor^{2

5}, Douglas Myers-Turnbull², Drew Young², Grant Burley¹, Lain X Pierce¹, Ryan E Hibbs⁴, David Kokel², Jason K Sello¹

Affiliations

¹ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
² Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94158, United States.
³ Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States.
⁴ Department of Neurobiology, University of California, San Diego, California 92093, United States.
⁵ UCSF Weill Institute for Neurosciences Memory and Aging Center, University of California, San Francisco, California 94158, United States.

PMID: 39287508
DOI: 10.1021/acschemneuro.4c00426

Abstract

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.

Keywords: GABA; TSPO; anesthetics; electrophysiology; isoflavones; neuropharmacology; paradoxical excitation; phenotypic screening; startle response; structure activity relationship; zebrafish.