Journal article

DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in Vivo

Karen J Thompson, Elham Khajehali, Sophie J Bradley, Jovana S Navarrete, Xi Ping Huang, Samuel Slocum, Jian Jin, Jing Liu, Yan Xiong, Reid HJ Olsen, Jeffrey F Diberto, Kristen M Boyt, Melanie M Pina, Dipanwita Pati, Colin Molloy, Christoffer Bundgaard, Patrick M Sexton, Thomas L Kash, Michael J Krashes, Arthur Christopoulos Show all

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE | AMER CHEMICAL SOC | Published : 2018

Abstract

Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine-N-oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs..

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Grants

Awarded by Wellcome Trust Collaborative Award


Awarded by Intramural Research Program of the NIH, The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)


Awarded by MRC


Awarded by NINDS


Awarded by Cancer Research U.K. Beatson Institute


Funding Acknowledgements

These studies were funded by a Wellcome Trust Collaborative Award (201529/Z/16/Z) (A.B.T., A.C., K.J.T., and E.K.). This work was supported by the Intramural Research Program of the NIH, The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), DK075087 (M.J.K.), DK075089 (M. J. K.), U24DK116195 (B. L. R.), UO1MH105892 (B.L.R., J.J., and T.K.) and the NIMH Psychoactive Drug Screening Program (X.P.H., S.S., and B.L.R.). S.J.B. is funded through a Lord Kelvin Adam Smith Fellowship and an MRC project grant (MR/P019366/1). R.H.J.O. is funded through the grant NRSA F31-NS093917, NINDS. We acknowledge the BSU facilities at the Cancer Research U.K. Beatson Institute (C596/A17196) and the Biological Services at the University of Glasgow. We are grateful to Emma Barr for support of the Tobin group.