Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice

Muscarinic Designer Receptors Exclusively Activated by Designer Drugs (DREADD) gated by clozapine-N-oxide (CNO) allow selective G-protein cascade activation in genetically specified cell-types in vivo . Here we compare the pharmacokinetics, off-target effects and efficacy of CNO, clozapine (CLZ) and...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports Vol. 9; no. 1; p. 4522
Main Authors: Jendryka, Martin, Palchaudhuri, Monika, Ursu, Daniel, van der Veen, Bastiaan, Liss, Birgit, Kätzel, Dennis, Nissen, Wiebke, Pekcec, Anton
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 14.03.2019
Nature Publishing Group
Subjects:
14/19
631/378/2649/2150
64/60
692/4017
82/80
96/106
Acetylcholine receptors (muscarinic)
Animals
Bioavailability
Cell activation
Cells, Cultured
Cerebrospinal fluid
Clozapine
Clozapine - analogs & derivatives
Clozapine - analysis
Clozapine - metabolism
Clozapine - pharmacokinetics
Drug dosages
Half-Life
Humanities and Social Sciences
Ligands
Male
Metabolites
Mice
Mice, Inbred C57BL
multidisciplinary
Neurons - cytology
Neurons - metabolism
Pharmacodynamics
Pharmacokinetics
Piperazines - analysis
Piperazines - metabolism
Piperazines - pharmacokinetics
Plasma
Proteins
Rats
Rats, Sprague-Dawley
Science
Science (multidisciplinary)
ISSN:2045-2322, 2045-2322
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Muscarinic Designer Receptors Exclusively Activated by Designer Drugs (DREADD) gated by clozapine-N-oxide (CNO) allow selective G-protein cascade activation in genetically specified cell-types in vivo . Here we compare the pharmacokinetics, off-target effects and efficacy of CNO, clozapine (CLZ) and compound 21 (Cmpd-21) at the inhibitory DREADD human Gi-coupled M4 muscarinic receptor (hM4Di). The half maximal effective concentration (EC 50 ) of CLZ was substantially lower (0.42 nM) than CNO (8.1 nM); Cmpd-21 was intermediate (2.95 nM). CNO was back-converted to CLZ in mice, and CLZ accumulated in brain tissue. However, CNO itself also entered the brain, and free cerebrospinal fluid (CSF) levels were within the range to activate hM4Di directly, while free (CSF) CLZ levels remained below the detection limit. Furthermore, directly injected CLZ was strongly converted to its pharmacologically active metabolite, norclozapine. Cmpd-21 showed a superior brain penetration and long-lasting presence. Although we identified a wide range of CNO and Cmpd-21 off-targets, there was hardly any nonspecific behavioural effects among the parameters assessed by the 5-choice-serial-reaction-time task. Our results suggest that CNO (3–5 mg/kg) and Cmpd-21 (0.4–1 mg/kg) are suitable DREADD agonists, effective at latest 15 min after intraperitoneal application, but both require between-subject controls for unspecific effects.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-41088-2