DREADD Ligands

Supporting information

DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are genetically modified G-protein coupled receptors (GPCRs) that are activated by physiologically inert designer synthetic ligands (designer drugs). Studies have provided evidence that DREADDs are functionally similar to their wild type receptors, therefore they are useful tools for the study of GPCR signaling.

The first DREADDs to be developed were derived from human muscarinic acetylcholine receptors (mAChRs) and termed hM1-5D. These receptors have mutations in their orthosteric binding site, abolishing their affinity for the endogenous ligand ACh, while rendering them responsive to the small molecule clozapine-N-oxide (CNO). CNO exhibits no appreciable affinity (Ki >1 μM) for any other relevant CNS target, and therefore is a selective tool for the activation of DREADDs.

DREADD Ligands Mechanism of Action

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DREADD Ligands Mechanism of Action.

Figure 1: Schematic outlining the mechanism of action of DREADD ligand signaling through DREADDs. DREADD ligands that induce Gq signaling provoke neuronal firing, whereas those that induce Gi signaling cause neuronal silencing. Clozapine N-oxide is a non-selective muscarinic DREADD agonist, which activates Gq-mediated signaling on binding to M1, M3 and M5 DREADDs, and Gi-mediated signaling on binding to M2 and M4 DREADDs.

DREADDs have been shown to be effective for the modulation of neuronal activity. hM3Dq is a Gq-coupled GPCR that activates neuronal firing upon CNO stimulation, while hM4Di is a Gi-coupled GPCR that inhibits neuronal firing through activation of GIRK (Kir3) channels. These DREADDs have also been shown to have applications in vivo. Activation of hM3Dq expressing locus coeruleus neurons by CNO enhanced memory in a mouse model of Down syndrome. Furthermore injection of hM3Dq into the paraventricular hypothalamus (PVH) suppressed hyperphagia in PVH LMO4-deficient obese mice, with activation of hM4Di having the opposite effect.

A new DREADD has since been developed from the κ opioid receptor (KOR), and termed KORD. KORD is activated by the pharmacologically inert small molecule salvinorin B, and will enable the simultaneous interrogation of KOR and mAChR signaling. The development of further DREADDs and small molecule DREADD modulators is currently ongoing.

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Literature for DREADD Ligands

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