7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity.
The effects of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2 (1H)- quinolinone (OPC-14597), a derivative of the dopamine (DA) autoreceptor agonist 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392), on DA receptors were biochemically and behaviorally studied and compared with those of OPC-4392. Both OPC-14597 and OPC-4392 inhibited reserpine- and gamma-butyrolactone (GBL)-induced increase in tyrosine hydroxylase activity in the mouse and rat brain. The effects of OPC-14597 were comparable to those of OPC-4392 and were completely antagonized by haloperidol. OPC-14597, unlike apomorphine, did not evoke postsynaptic DA receptor-stimulating behavioral signs such as hyperlocomotion in the reserpinized mice and contralateral rotation in rats with unilateral striatal 6-hydroxydopamine lesions. Both OPC-14597 and OPC-4392 inhibited such apomorphine-induced postsynaptic behavioral changes as stereotypy and hyperlocomotion in mice and rats and rotation in rats with unilateral striatal kainic acid lesions. The anti-apomorphine effects of OPC-14597 were about 30 to 140 times greater than those of OPC-4392 and were observed at doses that inhibit the increases in tyrosine hydroxylase activity. The affinities of OPC-14597 for 3H-spiperone-labeled D2 receptors in the rat frontal cortex, limbic forebrain and striatum were higher than those of OPC-4392. These results suggest that OPC-14597 is a unique antipsychotic drug candidate, being a DA autoreceptor agonist that has a stronger postsynaptic D2 receptor antagonistic activity than that of OPC-4392.
Kikuchi
T
T
Third Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd, Japan.
Tottori
K
K
Uwahodo
Y
Y
Hirose
T
T
Miwa
T
T
Oshiro
Y
Y
Morita
S
S
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D000068180:Aripiprazole; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D012110:Reserpine / Q000494:pharmacology; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D015363:Quinolones; D014316:Tritium; D013134:Spiperone; D004295:Dihydroxyphenylalanine; D000068180:Aripiprazole; D012110:Reserpine; D016627:Oxidopamine; D001058:Apomorphine; D015107:4-Butyrolactone