Ultrapotent chemogenetics for research and potential clinical applications

• Type of Material: Article
• Authors: Christopher J. Magnus, Howard Hughes Medical Institute; Peter H. Lee, Howard Hughes Medical Institute; Jordi Bonaventura, National Institute on Drug Abuse; Roland Zemla, New York University; Juan L. Gomez, National Institute on Drug Abuse; Melissa Ramirez, Howard Hughes Medical Institute; Xing Hu, Emory University; Adriana Galvan, Emory University; Jayeeta Basu, New York University; Michael Michaelides, National Institute on Drug Abuse; Scott M. Sternson, Howard Hughes Medical Institute
• Language: English
• Date: 2019-04-12
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Association for the Advancement of Science. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.aav5282
• Title of Journal or Parent Work: Science
• Volume: 364
• Issue: 6436
• Start Page: 146
• End Page: +
• Grant/Funding Information: S.M.S., C.M., P.L., and M.R. were funded by HHMI. X.H. and A.G. was supported by grant NIH ORIP OD P51-OD011132 to the Yerkes National Primate Research Center.; J.B. was supported by the Alfred P. Sloan Foundation, Klingenstein-Simons Foundation, NIH NINDS 1R01 NS109362–01, and Whitehall Foundation. M.M. is funded through NIDA IRP (ZIA000069).
• Keywords: Science & Technology; Multidisciplinary Sciences; Discriminative stimulus; Science & Technology - Other Topics; Neurons; Alpha-4 beta-2; Partial agonists; In-vivo; Smoking cessation; Whole blood; Nicotinic acetylcholine receptors; Varenicline; Global pallidus
• Research Categories: Biology, Genetics; Biology, Neuroscience; Biology, Molecular; Chemistry, Biochemistry

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.