dironyl and Schizophrenia

Terguride, a partial dopamine agonist, was administered in a 4-week open clinical trial to 17 schizophrenic patients suffering from extrapyramidal side effects of neuroleptic treatment. The neuroleptic dosage was kept constant. The mean final daily dose of terguride reached 3.4 mg (SD = 2.0). Fourteen patients completed the trial. Total scores on the Rating Scale for Extrapyramidal Side Effects and the Brief Psychiatric Rating Scale showed a significant improvement of 69% and 40%, respectively. There was also a significant improvement in all BPRS factor scores.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Dopamine Agents; Dyskinesia, Drug-Induced; Female; Humans; Lisuride; Male; Middle Aged; Neurologic Examination; Parkinson Disease, Secondary; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Eleven schizophrenics (7 females) displaying an acute psychotic episode received the partial dopamine agonist terguride in doses up to 2 mg per day. Improvement in terms of positive symptoms reduction was observed in two cases only. In contrast, in a previous clinical trial targeted at negative schizophrenic symptoms, the majority of the patients appeared to have benefited from terguride application.

Topics: Adolescent; Adult; Antipsychotic Agents; Drug Evaluation; Female; Humans; Lisuride; Psychological Tests; Receptors, Dopamine; Schizophrenia; Schizophrenia, Paranoid

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Calcium Signaling; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunoblotting; Lisuride; MAP Kinase Signaling System; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1; Phosphorylation; Piperazines; Piperidines; Quinolones; Raclopride; Receptors, Dopamine D2; Schizophrenia; Time Factors; Transfection

Topics: Adult; Dopamine Agents; Ergolines; Humans; Lisuride; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology