By David R. Sibley & Lei Shi
Schizophrenia is a disorder that involves hallucinations, delusions and cognitive impairment, and that affects nearly 1% of the global population1. The mainstays of therapy have been drugs that block the activity of the D2 dopamine receptor (D2R), a member of the large G-protein-coupled receptor (GPCR) superfamily of membrane proteins. Unfortunately, most of these antipsychotic drugs come with a plethora of debilitating side effects, many of which are due to off-target interactions with other GPCRs. In a paper in Nature, Wang et al.2 now report the crystal structure of D2R in complex with the antipsychotic drug risperidone. The structure reveals features that might be useful for the design or discovery of drugs that have greater selectivity for D2R than existing therapeutics, and consequently have fewer side effects.
The naturally occurring ligand for D2R is a neurotransmitter called dopamine, which mediates various physiological functions, including the control of coordinated movement, cognition and the reinforcing properties of drugs of abuse. There are five receptors for dopamine, which fall into two subgroups on the basis of their associated intracellular signalling pathways and their affinities for various drugs3: D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R and D4R). As early as the 1970s, it was hypothesized that the therapeutic effects of antipsychotic drugs were due to them blocking D2-like, rather than D1-like, receptors4,5, but the existence of multiple D2-like receptors was not discovered until they were cloned some 15 years later6.
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