raclopride and dironyl

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

Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Binding, Competitive; Cell Membrane; CHO Cells; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; DNA, Complementary; Dopamine; Dopamine Agonists; Dopamine Antagonists; Haloperidol; Humans; Lisuride; Piperazines; Piperidines; Quinolones; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Risperidone; Transfection; Tritium

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.

Topics: Administration, Oral; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzothiazoles; Cebus; Disease Models, Animal; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Haloperidol; Lisuride; Male; Piperidines; Pramipexole; Quinpirole; Raclopride; Salicylamides; Thiazoles