Dopamine D4 receptors and development of newer antipsychotic drugs

The last ten years have witnessed the generation of a large amount of information on the neurobiology of dopamine receptors. Molecular biology and pharmacology studies have revealed existence of at least five dopamine receptor subtypes, namely D1, D2, D3, D4 and D5. The discovery of D4 receptors and the putative affinity of clozapine for D4 receptors have kindled development of selective D4 receptor antagonists for the treatment of schizophrenia. Studies on expression of D4 receptor proteins have shown selective localisation of D4 receptors in mesolimbic/mesocortical areas which could probably explain the lack of motor side effects with atypical antipsychotics like clozapine and olanzapine. However, neuropathological and genetic studies on the role of D4 receptors in the pathophysiology of schizophrenia and preliminary clinical studies with selective D4 receptor antagonists have been disappointing. There have been, however, complimentary findings between selective D4 receptor antagonism and genetic approaches such as antisense treatment or gene targeting. The therapeutic potential of D4 receptors as a target for developing antipsychotics will be known only when selective D4 receptor-antagonists with varying D2/D4 and D4/5-HT2A ratios are developed and tested in psychiatric patients.