Subtype-selective agents for the dopamine D3 receptor (D3R) are implicated as potential medications for drug addiction and other neuropsychiatric disorders.  Previous medicinal chemistry efforts together with structure-activity relationship studies have led to the discovery of 4-phenylpiperazine derivatives that are >100-fold selective for D3R over D2R.  This class of compounds has a 4-phenylpiperazine moiety that binds to the orthosteric site, and an extended aryl amide moiety, connected via a butyl linking chain.  We modeled the binding modes of several of these compounds in D3R and D2R by comparative ligand docking and MD simulations.  We found that the aryl amide moiety of the ligand interacts with a hydrophobic pocket near TM2 in D3R, whereas it is not optimally positioned to interact with this pocket in D2R.    We subsequently carried out a receptor chimera study, followed by site-directed mutagenesis experiments to validate the binding mode and to identify specific residues that are responsible for differential conformations of the hydrophobic pocket in D3R and D2R.

Structural basis for dopamine D3 receptor subtype-selectivity

243rd National Meeting (2012)

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