as Compound 21, represents an alternative agonist for muscarinic-based DREADDs and an alternative to CNO. It has been reported that Compound 21 has excellent bioavailability, pharmacokinetic properties and brain penetrability and does not undergo reverse metabolism to clozapine. Another known agonist is perlapine, a hypnotic drug approved for treating insomnia in Japan. It acts as an activator of Gq-, Gi-, and Gs DREADDs that has structural similarity to CNO. A more recent agonist of hM3Dq and hM4Di is deschloroclozapine (DCZ). On the other hand, SalB B is a potent and selective activator of KORD. JHU37160 and JHU37152 have been marketed commercially as novel DREADD ligands, active in vivo, with high potency and affinity for hM3Dq and hM4Di DREADDs. Diihydrochloride salts of DREADDs ligands that are water-soluble (but with differing stabilities in solution) have also been commercially developed (see for aqueous stability). Mechanism RASSLs and DREADDs are families of designer G-protein-coupled receptors (GPCRs) built specifically to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called RASSLs (receptors activated solely by synthetic ligands), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the interrogation of several GPCR signaling pathways, including those activated by Gs, Gi, Gq, Golf and β-arrestin. A major cause for success of RASSL resources has been open exchange of DNA constructs, and RASSL related resources. The hM4Di-DREADD's inhibitory effects are a result of the CNO's stimulation and resulting activation of the G-protein inwardly rectifying potassium (GIRK) channels. This causes hyperpolarization of the targeted neuronal cell and thus attenuates subsequent activity. Uses This chemogenetic technique can be used for remote manipulation of cells, in particular excitable cells like neurons, both in vitro and in vivo with the administration of specific ligands. Similar techniques in this field include thermogenetics and optogenetics, the control of neurons with temperature or light, respectively. Viral expression of DREADD proteins, both in-vivo enhancers and inhibitors of neuronal function, have been used to bidirectionally control behaviors in mice (e.g odor discrimination). Due to their ability to modulate neuronal activity, DREADDs are used as a tool to evaluate both the neuronal pathways and behaviors associated with drug-cues and drug addiction. History Strader and colleagues designed the first GPCR which could be activated only by a synthetic compound and has gradually been gaining momentum. The first international RASSL meeting was scheduled