Return of D 4 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 D1-3,5 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.