新型突触前多巴胺D2受体激动剂7-(3-[4-(2,3-二甲基苯基)哌嗪基]丙氧基)-2(1H)-喹啉酮(OPC-4392)对大鼠纹状体切片中酪氨酸羟化作用的影响。

Effect of 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)- 2(1H)-quinolinone (OPC-4392), a newly synthesized agonist for presynaptic dopamine D2 receptor, on tyrosine hydroxylation in rat striatal slices.

作者信息

Kiuchi K, Hirata Y, Minami M, Nagatsu T

机构信息

Department of Biochemistry, Nagoya University School of Medicine, Japan.

出版信息

Life Sci. 1988;42(3):343-9. doi: 10.1016/0024-3205(88)90644-3.

DOI:10.1016/0024-3205(88)90644-3

PMID:2892110

Abstract

The effects of a newly synthesized compound, 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392), on tyrosine hydroxylation in situ and in vitro were studied using rat striatal slices and tyrosine hydroxylase (TH) purified from bovine adrenal medulla, respectively. OPC-4392 dose-dependently inhibited L-dihydroxyphenylalanine (DOPA) formation in rat striatal slices with IC50 values of about 10(-6) M. The inhibitory effect of OPC-4392 on in situ DOPA formation was dose-dependently reversed by addition of sulpiride, a dopamine D2 receptor antagonist, whereas no change was observed by addition of nomifensine (5 X 10(-6) M), a blocker of dopamine uptake. From in vitro experiment using purified TH, OPC-4392 affected neither the enzymatic activity nor the Km value for 6-methyl-5,6,7,8-tetrahydropterin (6MPH4). These results suggest that OPC-4392 impairs in situ DOPA formation by stimulating presynaptic dopamine D2 receptor as a dopamine agonist, and not by directly inhibiting the TH activity.

摘要

分别使用大鼠纹状体切片和从牛肾上腺髓质纯化的酪氨酸羟化酶（TH），研究了一种新合成的化合物7-(3-[4-(2,3-二甲基苯基)哌嗪基]丙氧基)-2(1H)-喹啉酮（OPC-4392）对原位和体外酪氨酸羟化的影响。OPC-4392剂量依赖性地抑制大鼠纹状体切片中L-二羟基苯丙氨酸（DOPA）的形成，IC50值约为10^(-6) M。多巴胺D2受体拮抗剂舒必利的加入可剂量依赖性地逆转OPC-4392对原位DOPA形成的抑制作用，而多巴胺摄取阻滞剂诺米芬辛（5×10^(-6) M）的加入则未观察到变化。从使用纯化TH的体外实验来看，OPC-4392既不影响酶活性，也不影响6-甲基-5,6,7,8-四氢蝶呤（6MPH4）的Km值。这些结果表明，OPC-4392作为多巴胺激动剂，通过刺激突触前多巴胺D2受体而损害原位DOPA的形成，而非直接抑制TH活性。