Designer Receptor Exclusively Activated by Designer Drugs (DREADD) (DREADD)

Chemogenetic receptors are engineered proteins, primarily Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that allow for the precise control of cellular signaling through the administration of synthetic, otherwise inert ligands (Roth, B. L., Neuron, 2016). These receptors are typically derived from human G protein-coupled receptors (GPCRs), such as muscarinic receptors, which have been mutated to lose affinity for their endogenous ligand while gaining high potency for a designer molecule like clozapine N-oxide (CNO) or deschloroclozapine (DCZ) (Armbruster et al., PNAS, 2007). When expressed in specific tissues via viral vectors or transgenics, they enable researchers and clinicians to modulate physiological processes—such as neuronal firing or metabolic activity—with high spatial and temporal resolution (Sternson & Roth, Annu Rev Neurosci, 2014). While extensively used as research tools to map functional neuroanatomy, they are increasingly viewed as potential therapeutic platforms for treating neurological disorders like epilepsy and Parkinson's disease by providing on-demand modulation of dysfunctional circuits (Urban & Roth, Annu Rev Pharmacol Toxicol, 2015). The clinical translation of this technology faces challenges including the potential metabolic conversion of ligands and the long-term safety of transgene expression, but it remains a frontier in precision medicine and gene therapy (Gomez et al., Science, 2017). Beyond GPCRs, the field has expanded to include ligand-gated ion channels, such as Pharmacologically Selective Actuator Modules (PSAMs), which respond to drugs like varenicline (Magnus et al., Science, 2011).

Other names

Chemogenetic receptorRASSLReceptor Activated Solely by Synthetic LigandEngineered receptorPharmacogenetic receptorPSAMPharmacologically Selective Actuator Module

Activation of engineered G protein-coupled receptors or ion channels by synthetic, bio-orthogonal ligands to modulate intracellular signaling (Gq, Gi, or Gs pathways) or membrane potential (Urban & Roth, Annu Rev Pharmacol Toxicol, 2015).