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Science. 2019 Apr 12;364(6436). pii: eaav5282. doi: 10.1126/science.aav5282. Epub 2019 Mar 14.

Ultrapotent chemogenetics for research and potential clinical applications.

Author information

1
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
2
Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.
3
Neuroscience Institute, New York University, New York, NY 10016, USA.
4
Medical Scientist Training Program, New York University School of Medicine, New York, NY 10016, USA.
5
Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA 30329, USA.
6
Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, NY 10016, USA.
7
Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. sternsons@janelia.hhmi.org.

Abstract

Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a 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 smoking cessation drug varenicline. We then synthesized subnanomolar-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.

PMID:
30872534
DOI:
10.1126/science.aav5282
[Indexed for MEDLINE]

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