INTERACTION OF ANTIPSYCHOTIC-DRUGS WITH NEUROTRANSMITTER RECEPTOR-SITES IN-VITRO AND IN-VIVO IN RELATION TO PHARMACOLOGICAL AND CLINICAL EFFECTS - ROLE OF 5HT(2) RECEPTORS

In the introductory section an overview is given of the strategies whi ch have been proposed in the search for side-effect free antipsychotic s. Special attention is paid to the role of predominant 5HT2 receptor blockade over D2 blockade. Whereas D2 receptor blockade seems to be es sential for the treatment of positive symptoms of schizophrenia, it al so underlies the induction of extrapyramidal side effects (EPS). Predo minant 5HT2 receptor blockade may reduce the EPS liability and can ame liorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eig ht new antipsychotics that recently entered clinical trial, 5HT2 and D 2 receptor binding affinity (K(i) values) and the rank order in affini ty for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the c omplete receptor binding profile (including 33 radioligand receptor bi nding and neurotransmitter uptake models) is reported. Furthermore, fo r a series of 120 compounds the relative affinity for D2 receptors and D3 receptors (a recently cloned new dopamine receptor subtype) is com pared. Finally, original findings are reported for the new antipsychot ic risperidone and for haloperidol and clozapine on the in vivo occupa tion of neurotransmitter receptors in various brain areas after system ic treatment of rats or guinea pigs. The receptor occupation by the dr ugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the t est compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT2 and D2 receptor mediat ed effects. With risperidone a high degree of central 5HT2 receptor oc cupation was achieved before other neurotransmitter receptors became o ccupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D2 receptor-mediated effects w as achieved at widely varying degrees of D2 receptor occupancy, from j ust about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic e ffects may be achieved at a relatively low degree of D2 receptor occup ancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiat ion between the various D2 receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patient s.