P-9-12 - Pharmacological profile of PR-000608, a novel dopamine uptake inhibitor

Abstract

This chapter discusses the strategies for developing new antipsychotic drugs, as well as the problems in clinical schizophrenia research. Reports from clinical trials suggest possible improved activity profiles for several new dopamine (DA) antagonists. Remoxipride has been efficacious in the treatment of schizophrenia with fewer extrapyramidal side effects. A pharmacophore for DA D2 antagonist activity has been developed, based on the conformational properties of semi-rigid antipsychotic drugs. The biological mechanisms underlying the effects of clozapine continued to be an important area of research. The involvement of brain serotonin (5-hydroxytryptamine, 5-HT) systems in the etiology and drug therapy of schizophrenia is reviewed in the chapter. Zotepine, a potent 5-HT and DA antagonist, has been efficacious in clinical trials with paranoid, resistant, and negative schizophrenia. Umespirone has been found to be active in preclinical tests for antipsychotic and anxiolytic activity. Results from early clinical trials on DA autoreceptor agonists in schizophrenia have provided mixed results. While sigma ligands have been proposed as potential antipsychotics, the functional role of brain sigma binding sites remained an enigma. Studies of the brain DA D2 receptor from schizophrenics revealed no structural changes. A review considered the hypothesis that an imbalance between GABA and glutamate contributes to psychosis. Another review proposed that schizophrenia might result from alterations in the regulation of phasic and tonic components of brain DA release. Further studies on prepulse inhibition of acoustic startle have supported the selectivity of this procedure for identifying antipsychotic drugs. Amphetamine-induced release of DA from brain slices has been proposed as a biochemical model for psychosis.