DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDsin Vitroandin Vivo

• DOI: 10.1021/acsptsci.8b00012
• Publication Date: 2018-07-27T16:51:46Z
• Authors: Karen J. Thompson; Elham Khajehali; Sophie J. Bradley; Jovana S. Navarrete; Xi Ping Huang; Samuel Slocum; Jian Jin; Jing Liu; Yan Xiong; Reid H. J. Olsen; Jeffrey F. Diberto; Kristen M. Boyt; Melanie M. Pina; Dipanwita Pati; Colin Molloy; Christoffer Bundg...; Patrick M. Sexton; Thomas L. Kash; Michael J. Krashes; Arthur Christopoulos; Bryan L. Roth; Andrew B. Tobin
• Keywords: Muscarinic agonist

Chemogenetic tools such as designer receptors exclusively activated by drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family insensitive endogenous agonist but instead clozapine-N-oxide (CNO). Despite undisputed success CNO an activator DREADDs, it has been known for some time that is subject low rate metabolic conversion clozapine, raising need alternative chemical actuators muscarinic-based DREADDs. Here we show DREADD 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) potent selective at both excitatory (hM3Dq) inhibitory (hM4Di) excellent bioavailability, pharmacokinetic properties, brain penetrability. We also C21-induced activation hM3Dq hM4Di vivo can bidirectional feeding defined circuits mice. These results indicate C21 represents studies where clozapine concern.