Novel antipsychotic agents with dopamine autoreceptor agonist properties: synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives.
To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the gamma-butyrolactone (GBL)-induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-3,4-dihydro-2 (1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 mumol/kg p.o.) and inhibited the APO induced stereotypy (ED50 values of 0.6 mumol/kg p.o.). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mumol/kg p.o.).
Oshiro
Y
Y
Third Institute of New Drug Research, Otsuka Pharmaceutical Company Ltd., Tokushima, Japan.
Sato
S
S
Kurahashi
N
N
Tanaka
T
T
Kikuchi
T
T
Tottori
K
K
Uwahodo
Y
Y
Nishi
T
T
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D000068180:Aripiprazole; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D010879:Piperazines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D015363:Quinolones / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018757:GABA Modulators; D010879:Piperazines; D015363:Quinolones; D004295:Dihydroxyphenylalanine; D000068180:Aripiprazole; D001058:Apomorphine; D015107:4-Butyrolactone