Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As far as schizophrenia is concerned, therapeutical effects of neuroleptics based on brain-located dopamine receptor blockers are taken for granted. It is also admitted, however, that classical neuroleptics have inconveniences, namely: Their relative lack of effect on negative symptoms, and their liability to induce extrapyramidal symptoms (EPS). Pipamperone-based clinical studies evidenced that an antagonist combining serotonin 5-HT2, and dopamine D2 was successful in the treatment of schizophrenia--which could be clearly observed in (a) anti-autistic effects, (b) regulating disrupted sleep-wake rhythms, and (c) a lesser tendency to EPS. Setoperone-based studies--a compound with a comparable pharmacological profile--confirmed the above observations. Until, however, the synthesis of ritanserin--a specific, and selective antagonistic receptor--was not achieved, no exact implication of 5-HT2 antagonist in psychopharmacological treatments of schizophrenia could be explored further. Indeed, double-blind trials evidenced a remarkable improvement in negative as well as extrapyramidal symptoms. Since a monotherapy appeared as undeniably called for in the treatment of schizophrenia, the next logical step to be taken was selecting a compound with a central antagonism comparable to ritanserin's, and a central D2 antagonism comparable to haloperidol's. Among a chemical range of benzisoxazole derivatives, risperidone was thus selected. The first double-blind trials on chronic schizophrenic patients seem indeed to confirm that this substance is likely to get over the above mentioned inconveniences, so typical of classical neuroleptics.
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PMID:[Development of new antipsychotic drugs]. 212 39

The advent of receptor binding techniques has provided new ways of studying the mechanism of action of drugs. In vitro radioligand binding is now currently applied to investigate the specificity or multiple action of compounds. By using the same technique, the binding affinity of a drug can be measured for a variety of neurotransmitter, drug, peptide and ion channel receptor binding sites, providing the drug's receptor binding profile (LEYSEN et al. 1981; LEYSEN 1984). However, in vitro receptor binding is only the initial step in the investigation of drug-receptor interactions. Investigations in vivo are required to allow evaluation of how and where a drug acts. In fact, the study of drug-receptor interactions comprises three main stages: (a) in vitro radioligand receptor binding; (b) in vivo receptor binding, providing information on the accessibility of the drugs to the receptors localized in various central and peripheral tissues, on the drug potency for occupying various receptors, on the duration of receptor occupation and on the relationship between the degree of receptor occupation and pharmacological effects; and (c) the study of receptor regulation: the effect of chronic drug treatment on receptor alterations compared with alterations in functional responses in vivo. In this article, we will illustrate the three stages of investigation of receptor interactions and discuss the relevance and importance of the findings, using as examples three drugs known in psychopharmacological research: (a) the neuroleptic haloperidol, a prototype of a dopamine D2 antagonist: (b) Setoperone, a potential antipsychotic agent with very potent serotonin S2 and moderate D2 antagonistic activity (CEULEMANS et al. 1985; LEYSEN et al. 1986); and (c) ritanserin, a potent and long-acting S2 antagonist (LEYSEN et al. 1985), which has revealed therapeutic activity in dysthymia and negative symptoms of schizophrenia (REYNTJENS et al. 1986; GELDERS et al. 1986). Particular attention will be paid to the problem of receptor regulation. We challenge the general applicability of the receptor regulation theory, which states that persistent receptor stimulation causes desensitisation and receptor downregulation, whereas chronic deprivation of receptor stimulation leads to supersensitivity and receptor upregulation. Recent research has revealed that the theory does not hold for S2 receptor alterations, which were found to downregulate following chronic receptor blockade.
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PMID:Receptor interactions of dopamine and serotonin antagonists: binding in vitro and in vivo and receptor regulation. 304 96