期刊
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
卷 1, 期 1, 页码 61-72出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.8b00012
关键词
clozapine-N-oxide; clozapine; DREADD; designer receptors exclusively activated by designer drugs; muscarinic acetylcholine receptors
资金
- Wellcome Trust Collaborative Award [201529/Z/16/Z]
- Intramural Research Program of the NIH, The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK075087, DK075089, U24DK116195, UO1MH105892]
- NIMH Psychoactive Drug Screening Program
- Lord Kelvin Adam Smith Fellowship
- MRC [MR/P019366/1]
- NINDS [NRSA F31-NS093917]
- Cancer Research U.K. Beatson Institute [C596/A17196]
- MRC [MR/P019366/1] Funding Source: UKRI
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.
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