DREADD agonist 21 (Compound 21)
Effective agonist for muscarinic-based DREADDs in vitro and in vivo. Non-CNO chemogenetic actuator. Brain penetrant.
DREADD agonist 21 (Compound 21) represents an alternative chemogenetic actuator for muscarinic -based DREADDs and an alternative to CNO for in vivo studies in which metabolic conversion of CNO to clozapine is an issue.
DREADD agonist 21 (Compound 21) has excellent bioavailability, pharmacokinetic properties and brain penetrability. It has been reported that the compond does not undergo back metabolism to clozapine.
DREADD agonist 21 is a potent and selective agonist at muscarinic based DREADDs such as the excitatory hM3Dq, hM1Dq and inhibitory hM4Di DREADDs (pEC50 values are 8.48, 8.91 and 7.77 at hM3Dq, hM1Dq and hM4Di respectively). The compound exhibits >10-fold higher affinity at hM1Dq and hM4Di DREADDs compared to wild type receptors and also lacks agonist activity at wild type receptors.
In vivo use
DREADD agonist 21 from Hello Bio has recently been cited in a pharmacokinetic profile of the compound in mice by Jendryka et al (2019) which suggests that DREADD agonist 21 shows superior brain penetration and long-lasting presence. They suggest that the compound is a suitable DREADD agonist which is effective at latest 15 min after i.p injection, but requires between-subject controls for unspecific effects.
Figure: In vivo pharmacokinetic profile of DREADD agonist 21 (Cmpd-21). DREADD agonist 21 was from Hello Bio.
(j–l): Concentration (nM) of Cmpd-21 (blue) at 15, 30 and 60 min after i.p. injection of 3.0 mg/kg Cmpd-21 in (j) plasma, (k) CSF, and (l) cortical brain tissue. Reproduced from Jendryka et al Sci Rep. 2019;9(1):4522
DREADD agonist 21 (Compound 21)-induced activation of hM3Dq and hM4Di can modulate bi-directional feeding in defined circuits in mice. Concentrations of DREADD agonist 21 that resulted in changes in feeding behavior in animals expressing muscarinic DREADDs had no off-target effects in control animals (where musarinic DREADDs were not expressed).
Off target binding
DREADD agonist 21 shows weak to moderate binding affinity at a range of wild type GPCRs which may translate to functional antagonism in vivo.
Therefore care should be taken with in vivo dosing of DREADD agonist 21 to ensure the free concentration of the compound remains in a range that activates muscarinic DREADDs but is sufficiently low to avoid antagonism at wild type GPCRs.
Strong competitive binding of DREADD agonist 21 (Cmpd-21) to receptor sites of dopamine, 5-HT, opioid, muscarinic, histamine and adrenoceptors in mice has been shown. Only very subtle, if any behavioural alterations using the 5-CSRTT assessment were found Jendryka et al (2019).
In vivo experiments should be conducted with the appropriate controls where DREADD agonist 21 is administered to animals that do not express the muscarinic-DREADDs.
Data from a poster presented at SfN by the Michaelides group indicates that DREADD agonist 21 (Compound 21) has lower binding affinity for DREADDs compared to clozapine and that DREADD agonist 21 induces behavioural effects in transgenic mice. 1mg/kg doses were used. High doses (10mg/kg) may cause sedation.
Storing and Using Your Product
Soluble in DMSO (100mM) and in ethanol (100mM)
This product is for RESEARCH USE ONLY and is not intended for therapeutic or diagnostic use. Not for human or veterinary use
References for DREADD agonist 21 (Compound 21)
The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs.Chen et al (2015) ACS Chem Neurosci 6(3) : 476-84PubMedID: 25587888
Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits.Spangler and Bruchas (2017) Curr Opin Pharmacol 32 : 56-70.PubMedID: 27875804
Clozapine N-Oxide Administration Produces Behavioral Effects in Long-Evans Rats: Implications for Designing DREADD Experiments.MacLaren et al (2016) eNeuro 3(5) : 0219-16PubMedID: 27822508
New non-CNO actuators for DREADDsRoth Bl (2015) Blog : N/A
DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in VivoThompson et al (2018) ACS Pharmacol. Transl. Sci. 10.1021 : /acsptsci.8b00012
Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice.Jendryka et al (2019) Sci Rep. 9(1) : 4522PubMedID: 30872749