Signal Transduction

A drug's two-part way to block dopamine

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Science  05 Sep 2014:
Vol. 345, Issue 6201, pp. 1132
DOI: 10.1126/science.345.6201.1132-b

The dopamine receptor DR2 is a potential target for antipsychotic drugs. A new study reports an unusual mechanism of action for a small molecule that targets DR2. The core structure of the molecule, called SB26952, suggests it would bind to the same place as dopamine (the orthosteric site). Instead, however, it acts like an allosteric inhibitor—that is, an inhibitor that binds to a secondary (allosteric) site on DR2, preventing dopamine from binding to the orthosteric site. Campbell et al. now report that SB26952 binds to both the orthosteric and allosteric sites in one DR2 molecule, which is part of a pair. This inhibits dopamine binding to the orthosteric site of the second DR2 molecule.

Nat. Chem. Biol. 10.1038/nchembio.1593 (2014).

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