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Ultrapotent chemogenetics for research and potential clinical applications.

A figure from this study

A figure from this study

Hot Off the Press – April 12, 2019.

NIDA-funded scientists have just published findings in the journal Science showing the development of a new, groundbreaking chemogenetics technology for modulating brain function in a remote, precise and ultra-sensitive manner in living subjects. These findings describe new chemogenetic ion channels for neuron activation and silencing that are controlled by very low doses of the anti-smoking medication varenicline. This drug is an especially attractive molecule for chemogenetic applications in part because it is well-tolerated by patients, effectively penetrates the brain, and has long-lasting effects. This technique for modulating neuronal function, reported in laboratory animals, has potential for use in humans, and may pave the way for new treatments for addiction, pain, depression, and other conditions. Ongoing experiments at NIDA are already applying this technology to study malfunctioning brain circuits and their relevance to development of drug addiction.

The work was funded by NIDA; participating scientists were from NIDA’s Intramural Research program in Baltimore, Janelia: Howard Hughes Medical Institute’s Janelia Research Campus, New York University, Emory University and the Johns Hopkins School of Medicine

Publication Information

Magnus, Christopher J; Lee, Peter H; Bonaventura, Jordi; Zemla, Roland; Gomez, Juan L; Ramirez, Melissa H; Hu, Xing; Galvan, Adriana; Basu, Jayeeta; Michaelides, Michael; Sternson, Scott M

Ultrapotent chemogenetics for research and potential clinical applications. Journal Article

In: Science, 2019, ISSN: 1095-9203 (Electronic); 0036-8075 (Linking).

Abstract | Links

@article{Magnus:2019aa,
title = {Ultrapotent chemogenetics for research and potential clinical applications.},
author = {Christopher J Magnus and Peter H Lee and Jordi Bonaventura and Roland Zemla and Juan L Gomez and Melissa H Ramirez and Xing Hu and Adriana Galvan and Jayeeta Basu and Michael Michaelides and Scott M Sternson},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30872534},
doi = {10.1126/science.aav5282},
issn = {1095-9203 (Electronic); 0036-8075 (Linking)},
year = {2019},
date = {2019-03-14},
journal = {Science},
address = {Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.},
abstract = {Chemogenetics enables non-invasive chemical control over cell populations in behaving animals. However, existing small molecule agonists show insufficient potency or selectivity. There is also need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the anti-smoking drug varenicline. We then synthesized novel sub-nanomolar potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

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Chemogenetics enables non-invasive chemical control over cell populations in behaving animals. However, existing small molecule agonists show insufficient potency or selectivity. There is also need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the anti-smoking drug varenicline. We then synthesized novel sub-nanomolar potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.

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  • https://www.ncbi.nlm.nih.gov/pubmed/30872534
  • doi:10.1126/science.aav5282

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