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
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
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DOI：
10.1021/jm940608g
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发表时间：
1998-02-26
影响因子：
7.3
通讯作者：
Nishi, T
中科院分区：
文献类型：
--
作者：
Oshiro, Y;Sato, S;Nishi, T
为了研制一种新型多巴胺（DA）受体激动剂和突触后DA受体拮抗剂，合成了一系列7-[4-[4-（取代苯基）-1-哌嗪基]丁氧基]-3,4-二氢-2(1H)-喹啉酮类药物，并测定了它们的双重活性。化合物的突触后DA受体拮抗剂活性是通过抑制阿波啡诱导小鼠的刻板印象来评估的，而自身受体激动剂活性是通过其对γ -丁内酯（GBL）诱导的小鼠脑内l -二羟基苯丙氨酸（DOPA）合成增加的影响来评估的。许多化合物抑制了刻板行为，一些化合物逆转了凝胶诱导的多巴合成的增加。其中，7-[4-[4-（2,3-二氯苯基）-1-哌嗪基]-丁氧基]-3,4-二氢-2(1H)-喹啉酮（28，阿立哌唑，OPC-14597）具有这两种活性。该化合物逆转了gbl诱导的DOPA合成（ED50值为5.1 μ mol/kg po），抑制了APO诱导的刻板化（ED50值为0.6 μ mol/kg po）。化合物28诱导猝厥的剂量是apo诱导刻板反应的10倍（ED50值为7.8 mu mol/kg po）。
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 GEL-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 mu mol/kg po) and inhibited the APO induced stereotypy (ED50 values of 0.6 mu mol/kg po). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mu mol/kg po).