新的选择性r5-HT1B受体拮抗剂NAS-181在大鼠脑中增强了5-HT代谢和合成速率。,Neuropharmacology

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新的选择性r5-HT1B受体拮抗剂NAS-181在大鼠脑中增强了5-HT代谢和合成速率。
Neuropharmacology ( IF 4.6 ) Pub Date : 2000-03-23 , DOI: 10.1016/s0028-3908(99)00173-2
C Stenfors ₁ , H Yu , S B Ross

Affiliation

NAS-181（（R）-（+）-2-（3-morpholinomethyl-2H-chromen-8-yl）oxymethyl-morpholine methylsulfonate）是新型大鼠5-羟色胺1B（r5-HT1B）受体拮抗剂，具有高选择性。检查了NAS-181对大鼠脑内5-HT代谢和合成的体内作用。5-HT代谢（以5-羟基吲哚乙酸（5-HIAA）/ 5-HT的比率衡量）在0.1至20 mg的剂量范围内在所分析的所有四个大脑区域（下丘脑，海马，额叶皮层和纹状体）呈剂量依赖性增加/ kg sc NAS-181。在注射后1小时，剂量为20mg / kg sc的5-HT代谢的增强最大，并且在注射后8小时但不是24小时仍然显着。NAS-181在剂量为0.3到20 mg / kg sc的情况下，通过抑制芳香族氨基酸脱羧酶活性后5-羟色氨酸（5-HTP）的积累来衡量5-HT合成速率，NAS-181竞争性地降低了该降低r5-HT1B受体激动剂anpirtoline在下丘脑，海马和额叶皮质引起的5-HT代谢异常。蒽醌对纹状体中的5-HT代谢没有影响。然而，蒽醌拮抗由NAS-181诱导的纹状体中5-HT代谢的增强。用NAS-181和5-HT1A受体拮抗剂WAY-100635联合治疗大鼠，与单独使用化合物相比，可增加5'-HT代谢。NAS-181在下丘脑，海马和额叶皮层中拮抗r5-HT1B受体激动剂anpirtoline引起的5-HT代谢下降。蒽醌对纹状体中的5-HT代谢没有影响。然而，蒽醌拮抗由NAS-181诱导的纹状体中5-HT代谢的增强。用NAS-181和5-HT1A受体拮抗剂WAY-100635联合治疗大鼠，与单独使用化合物相比，可增加5'-HT代谢。NAS-181在下丘脑，海马和额叶皮层中拮抗r5-HT1B受体激动剂anpirtoline引起的5-HT代谢降低。蒽醌对纹状体中的5-HT代谢没有影响。然而，蒽醌拮抗由NAS-181诱导的纹状体中5-HT代谢的增强。用NAS-181和5-HT1A受体拮抗剂WAY-100635联合治疗大鼠，与单独使用化合物相比，可增加5'-HT代谢。

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Enhanced 5-HT metabolism and synthesis rate by the new selective r5-HT1B receptor antagonist, NAS-181 in the rat brain.

NAS-181 ((R)-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl) oxymethyl-morpholine methanesulfonate) is a novel rat 5-hydroxytryptamine1B, (r5-HT1B) receptor antagonist with high selectivity. The in vivo effects of NAS-181 on 5-HT metabolism and synthesis in the rat brain were examined. 5-HT metabolism, measured as the ratio 5-hydroxyindoleacetic acid (5-HIAA)/5-HT, was dose-dependently increased in all four brain regions analysed (hypothalamus, hippocampus, frontal cortex and striatum) at doses 0.1 to 20 mg/kg s.c. NAS-181. The enhancement of 5-HT metabolism at the dose 20 mg/kg s.c. was maximal one hour after the injection and was still significant eight hours but not 24 hours after the injection. 5-HT synthesis rate measured as the accumulation of 5-hydroxytryptophan (5-HTP) after inhibition of the aromatic amino acid decarboxylase activity was also elevated by NAS-181 at doses 0.3 to 20 mg/kg s.c. NAS-181 competitively antagonised the decrease in 5-HT metabolism evoked by the r5-HT1B receptor agonist, anpirtoline, in hypothalamus, hippocampus and frontal cortex. Anpirtoline had no effect on 5-HT metabolism in striatum. However, anpirtoline antagonised the enhancement of 5-HT metabolism induced by NAS-181 in striatum. Combined treatment of rats with NAS-181 and the 5-HT1A receptor antagonist, WAY-100635, increased 5'-HT metabolism considerably more than when the compounds were given alone.

更新日期：2019-11-01

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