Selective Dopamine D4 Receptor Antagonists: Review ofStructure-Activity Relationships

Cloned in 1991, the human dopamine D4 receptor is found mainly in cortical and limbic areas of brain. Many chemically dissimilar D4 receptor-selective antagonists have been developed, initially stimulated by partial D4 receptorselectivity of the clinically superior antipsychotic agent clozapine. Implication of D4 receptor in the pathophysiology or treatment of idiopathic psychotic disorders, however, remains elusive. Moreover, L-745,870, a selective D4 antagonist, and fananserin, a mixed antagonist of D4 and 5-HT2 receptors, failed to show antipsychotic efficacy. Interest in D4 receptor pharmacology was re-kindled by the 1996 discovery that D4 receptor gene polymorphism is associated with attention deficit-hyperactivity disorder (ADHD) and related personality traits. D4 receptors are also implicated in mood disorders and the actions of psychostimulants. Development of many chemically dissimilar D4-selective antagonists has contributed to improved understanding of D4 receptor neurobiology. This review summarizes recent advances in the synthetic chemistry of D4 receptor antagonists, and considers selected neuropharmacological studies suggestive of their potential clinical applications.