DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo

Thompson, K. J. et al. (2018) DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo. ACS Pharmacology and Translational Science, 1(1), pp. 61-72. (doi: 10.1021/acsptsci.8b00012) (PMID:30868140) (PMCID:PMC6407913)

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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. Here we show that DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability. We also show that C21-induced activation of hM3Dq and hM4Di in vivo can modulate bidirectional feeding in defined circuits in mice. These results indicate that C21 represents an alternative to CNO for in vivo studies where metabolic conversion of CNO to clozapine is a concern.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Molloy, Mr Colin and Bradley, Dr Sophie and Thompson, Ms Karen and Tobin, Andrew
Authors: Thompson, K. J., Khajehali, E., Bradley, S. J., Navarrete, J. S., Huang, X. P., Slocum, S., Jin, J., Liu, J., Xiong, Y., Olson, R. H.J., Diberto, J. F., Boyt, K. M., Pina, M. M., Pati, D., Molloy, C., Bundgaard, C., Sexton, P. M., Kash, T. L., Krashes, M. J., Christopoulos, A., Roth, B. L., and Tobin, A. B.
Subjects:Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:ACS Pharmacology and Translational Science
Publisher:American Chemical Society
ISSN (Online):2575-9108
Published Online:27 July 2018
Copyright Holders:Copyright © 2018 The American Chemical Society
First Published:First published in ACS Pharmacology and Translational Science 1(1):61-72
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
750161Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY
750711MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.Andrew TobinMedical Research Council (MRC)MR/P019366/1RI MOLECULAR CELL & SYSTEMS BIOLOGY