Return of D₄ Dopamine Receptor Antagonists in Drug Discovery

The dopamine D₄ receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D₄, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D₄ antagonists that were developed for schizophrenia failed in the clinic. Thus, D₄ fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D₄ ligands with improved selectivity for D₄ against not only D_1-3,5 but also other biogenic amine targets have emerged, and D₄ is once again in the spotlight as a novel target for both addiction and Parkinson's disease (PD), as well as other emerging diseases. This report will review the historical data for D₄, review the known D₄ ligands, and then highlight new data supporting a role for D₄ inhibition in addiction, PD, and cancer.