DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in Vivo
| Autor: | Patrick M. Sexton, Elham Khajehali, Reid H.J. Olsen, Kristen M. Boyt, Karen J. Thompson, Samuel T. Slocum, Andrew B. Tobin, Colin Molloy, Melanie M. Pina, Christoffer Bundgaard, Michael J. Krashes, Bryan L. Roth, Xi Ping Huang, Arthur Christopoulos, Jeffrey F. DiBerto, Sophie J. Bradley, Jovana Navarrete, Thomas L. Kash, Yan Xiong, Jing Liu, Dipanwita Pati, Jian Jin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist medicine.drug_class Chemistry Inhibitory postsynaptic potential 3. Good health 03 medical and health sciences 030104 developmental biology 0302 clinical medicine In vivo Muscarinic acetylcholine receptor medicine Excitatory postsynaptic potential Pharmacology (medical) Receptor 030217 neurology & neurosurgery Acetylcholine Endogenous agonist medicine.drug |
| Zdroj: | ACS Pharmacology & Translational Science. 1:61-72 |
| ISSN: | 2575-9108 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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