DREADDs for studying GPCR signaling
GPCRs can be modified so that they only respond to a specific biologically inert chemical (a designer drug). These modified GPCRs are called Designer Receptors Exclusively Activated by Designer Drugs or “DREADDs”. Cells expressing the DREADD respond robustly to low concentrations of the designer molecule, whereas cells that do not express DREADD are unresponsive to the designer drug. DREADDs are functionally similar to their wild type receptors, therefore they are exciting tools for the study of GPCR signaling.
What are the advantages of DREADDs?
- You can selectively control different signaling pathways in neurons: depending on the DREADD you choose, you can precisely control Gq, Gi or Gs-signaling pathways.
- DREADDs and the designer drugs are non-toxic: After expressing DREADDs you can use the corresponding designer drug to modify the activity of neurons over days or months whilst keeping the neurons healthy.
- Using DREADDs and corresponding designer drugs allows you to modify neuronal activity non-invasively in in vivo models. A brain permeant designer drug can be administered peripherally (by injection, or orally for example) - it can then cross the blood-brain barrier to activate DREADD-expressing neurons.
DREADD ligands available from Hello Bio
Clozapine N-oxide (CNO) is an inert metabolite of the atypical antipsychotic clozapine, CNO potently activates muscarinic designer DREADD receptors (termed hM1-5D). These receptors have no affinity for the endogenous ligand acetylcholine (ACh), but are responsive to CNO. CNO has no significant affinity (Ki >1 μM) for other CNS targets. CNO stimulates hM3Dq (a Gq-coupled GPCR) to activate neuronal firing. In vivo, CNO activation of hM3Dq-expressing locus coeruleus neurons enhances memory in a mouse model of Down syndrome. Hello Bio offers water-soluble CNO dihydrochloride, and the freebase version of CNO (which is also water-soluble, but more difficult to handle in solution). For researchers wishing to use the freebase version, read our technical review on stability, solubility and use for CNO (freebase).
Recent findings suggest that systemically administered CNO does not readily cross the blood-brain-barrier in vivo, and converts to clozapine which activates DREADDs. Care must be taken in experimental design and proper controls should be incorporated. Hello Bio also offers clozapine and water-soluble clozapine dihydrochloride for researchers who wish to use clozapine in their controls.
Compound 21 (DREADD agonist 21) is an analog of clozapine N-oxide (CNO) which is a highly potent agonist at the excitatory hM3Dq DREADD. Compound 21 (DREADD agonist 21) has been indicated to have equivalent potency in vivo when compared with CNO but unlike CNO, has minimal off-target activity and is less likely to metabolise to clozapine. View Datasheet for Compound 21 (DREADD agonist 21) and the water soluble Compound 21 (DREADD agonist 21) dihydrochloride.
Perlapine is a potent and selective hM3Dq DREADD receptor agonist (EC50 = 2.8 nM) which shows >10,000 fold selectivity for hM3Dq compared to the hM3 muscarinic receptor. Perlapine also activates the inhibitory hM2Di and hM4Di DREADDs View Datasheet for Perlapine and the water soluble Perlapine dihydrochloride.
Salvinorin B is a brain penetrant, potent and selective activator of κ-opioid DREADD (KORD) (EC50 = 11.8 nM). It is selective for KORD over the endogenous κ opioid receptor and other related targets. In KORD-expressing mouse models it induces neuronal hyperpolarization, and modifies locomotor activity and feeding behavior. However, it displays no ataxic or analgesic effects in wild type mice. View Datasheet for salvinorin B.
Find out more with our DREADD mini-review
Read our latest mini-review on DREADDs. Written by our expert PhD qualified technical team, and endorsed by our Scientific Advisory Board, this mini-review summarizes some of the features of DREADDs and their ligands.
Featured DREADD related products
Cmpd101 is a novel, potent and selective G-protein coupled receptor kinase 2 and 3 (GRK2/GRK3) inhibitor (IC50 values are 35, 290 nM and 125 µM at GRK2, GRK3 and GRK5 respectively). It shows little activity at a broad range of other kinases. Membrane permeable, it can be used to study the roles of GRK2/3 in GPCR desensitization and other functions. Find out more…ACh muscarinic receptor ligands