Abstract
A variety of 1, 2, 3, 4-tetrahydroisoquinolin-4-ols (1-6) were prepared as part of our search for new norepinephrine (NE) potentiators and to clarify the structure-activity relationships. These compounds and some previously prepared compounds were compared with 2-methyl-4-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol (PI-OH) (1a) for ability to potentiate NE. The potency, for 2-substitution, was found to be in the order : Me>Et>iso-Pr>H. The comopunds substituted by a halogen atom at the para position in the 4-phenyl group of PI-OH showed greater activities than did PI-OH, and the observed order of potency for the substitution was Cl>Br>F>H. The compound (4) methylated at the hydroxy group in PI-OH had greatly diminished activity. Although the desoxy compound (6) of PI-OH potentiated the response to NE at low concentrations, the potentiation was progressively masked by an inhibitory activity as the concentration of 6 was increased. In addition, the 4-cyclohexyl analogue (5) failed to potentiate NE. These results show the importance of the β-phenylethanolamine skeleton of PI-OH for producing NE potentiation without accompanying inhibitory action. The racemic 4-chlorophenyl analogue (2a) was resolved by HPLC to (R)-(+)-2a and (S)-(-)-2a. The NE-potentiating activity was found to reside exclusively in (R)-(+)-2a, which had the highest activity among compounds tested in this study; the activity ratio was 25 at 3×10-6M. The antidepressant activity of racemic 2a was evaluated by a forced swimming test. The activity of racemic 2a on the reduction of total duration of immobility in rats forced to swim was about 10 times that of desipramine. Thus, compound 2a appears to be a candidate for a new antidepressant.
