D4/5-HT2A RECEPTOR ANTAGONISTS : LU-111995 AND OTHER POTENTIAL NEW ANTIPSYCHOTICS IN DEVELOPMENT

(5). Despite its potential to induce agranulocytosis, clozapine is considered a mainstay of therapy of schizophrenics, especially for otherwise treatment-resistant patients. Pharmacologically, clozapine differs in its receptor profile from typical antipsychotics by having high affinity for different neurotransmitter receptors such as histamine H1, serotonin 5-HT2, 5-HT6, 5-HT7, muscarinic acetylcholine, α-adrenoceptors, etc., while binding with only moderate affinity to the dopamine D2 receptor (6-10). For two decades or more the search for new antipsychotics has focused on efforts to copy the receptor profile of clozapine. These efforts resulted in drugs combining D2 and 5-HT2 antagonism, such as risperidone. The discovery of dopamine D3 and D4 receptors as members of the D2 receptor family has opened new perspectives for the search for new antipsychotic agents (1116). In particular, the D4 receptor appears to be a promising target, since of all the dopamine receptors, clozapine exhibits highest affinity for this subtype. In addition, its ratio of D4 affinity over the free plasma concentration at therapeutic doses fits well with that of other neuroleptics (17). Investigations on D4 receptor mRNA distribution in rats revealed a preferential location in cortical and midbrain regions such as the amygdala and hippocampus. In primate brains, D4 receptor antibody labelling and binding was found on pyramidal cells as well as on interneurones of the cortex and the hippocampus (18). These areas have been linked to schizophrenic symptoms, especially negative symptoms and cognitive deficit. Only low density is detected in the corpus striatum (13-16, 19-21), believed to be the region in which D2 receptor antagonism causes EPS. Furthermore, D4 receptor levels were reported to be elevated in postmortem brains of schizophrenics (22, 23), although evidence for this finding is still under debate (24-27). Difficulties arise in defining and quantifying typical and CONTENTS

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