酚类2-甲基-4-苯基-1,2,3,4-四氢异喹啉-4-醇作为新型去甲肾上腺素增强剂的合成与药理评价

Synthesis and pharmacological evaluation of phenolic 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols as a new norepinephrine potentiator.

作者信息

Kihara M, Ikeuchi M, Kobayashi Y, Nagao Y, Hashizume M, Moritoki H

机构信息

Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.

出版信息

Drug Des Discov. 1994 Apr;11(3):175-83.

PMID:7548633

Abstract

2-Methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline-4-ol(PI-OH) (2a) and its derivatives form a new class of compounds possessing norepinephrine (NE) potentiating activity. As a new series of compounds, the isomeric 4-(4-hydroxyphenyl)- and 4-(3-hydroxyphenyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-4-ols (3a and 3b), and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolin-4-ol (3c) were prepared and their NE potentiating activities were evaluated. The 4-(4-hydroxyphenyl) analogue (3a) had only moderate activity and the 4-(3-hydroxyphenyl) analogue (3b) possessed a slightly higher activity than PI-OH. The 4-(3,4-dihydroxyphenyl) analogue (3c) was the most active compound and the pD2 value was 7.71 +/- 0.06 (activity ratio; 26.9 fold) at a concentration of 3 x 10(-6) M. These results indicate the importance of dihydroxyphenylethanolamine moiety of 3c for the inhibition of NE uptake.

摘要

2-甲基-4-苯基-1,2,3,4-四氢异喹啉-4-醇（PI-OH）（2a）及其衍生物构成了一类具有去甲肾上腺素（NE）增强活性的新型化合物。作为一系列新的化合物，制备了异构体4-（4-羟基苯基）-和4-（3-羟基苯基）-2-甲基-1,2,3,4-四氢异喹啉-4-醇（3a和3b）以及4-（3,4-二羟基苯基）-1,2,3,4-四氢异喹啉-4-醇（3c），并评估了它们的NE增强活性。4-（4-羟基苯基）类似物（3a）仅具有中等活性，4-（3-羟基苯基）类似物（3b）的活性略高于PI-OH。4-（3,4-二羟基苯基）类似物（3c）是活性最高的化合物，在浓度为3×10⁻⁶ M时，pD2值为7.71±0.06（活性比；26.9倍）。这些结果表明3c的二羟基苯乙醇胺部分对抑制NE摄取的重要性。