Dopamine D-4 receptors and development of newer antipsychotic drugs

The last ten years have witnessed the generation of a large amount of infor mation on the neurobiology of dopamine receptors. Molecular biology and pha rmacology studies have revealed existence of at least five dopamine recepto r subtypes. namely D-1, D-2, D-3, D-4 and D-5. The discovery of D-4 recepto rs and the putative affinity of clozapine for D-4 receptors have kindled de velopment of selective D-4 receptor, antagonists For the treatment of schiz ophrenia. Studies on expression of D-4, receptor proteins have shown select ive localisation of D-4, receptors in mesolimbic/mesocortical areas which c ould probably explain the lack of motor side effects with atypical antipsyc hotics like clozapine and olanzapine. However, neuropathological and geneti c studies on the role of D-4, receptors in the pathophysiology of schizophr enia and preliminary clinical studies with selective D-4 receptor antagonis ts have been disappointing. There have been, however, complimentary finding s between selective D-4, receptor antagonism and genetic approaches such as antisense treatment or gene targeting. The therapeutic potential of D-4, r eceptors as a target for developing antipsychotics will be known only when selective D-4 receptor antagonists with varying D-2/D-4 and D-4/5-HT2A rati os are developed and tested in psychiatric patients. (C) 2000 Editions scie ntifiques et medicales Elsevier SAS.