Synthesis and pharmacological evaluation of phenolic 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols as a new norepinephrine potentiator.
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.
Kihara
M
M
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Ikeuchi
M
M
Kobayashi
Y
Y
Nagao
Y
Y
Hashizume
M
M
Moritoki
H
H
D000818:Animals; D004298:Dopamine / Q000494:pharmacology; D004357:Drug Synergism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D007546:Isoquinolines; D014662:Vasoconstrictor Agents; D004298:Dopamine; D009638:Norepinephrine