SYNTHESIS AND ENANTIOSELECTIVITY OF OPTICALLY-ACTIVE 1-SUBSTITUTED AND 3-SUBSTITUTED 4-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLIN-4-OLS AND RELATED-COMPOUNDS AS NOREPINEPHRINE POTENTIATORS

Optically active ethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols (1 R,4R-3a and 1S,4S-3b, 1S,4R-4a, and 1R,4S-4b) and 2-methyl-4-phenyl-1, 2,3,4-tetrahydroisoquinolines (4S-5a and 4R-5b) were prepared in order to examine the effects of the 1-, 3-, and 4-substituents of methyl-4- phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (1) on the enantiose lectivity for norepinephrine (NE) potentiating activity. The conformat ions and absolute configurations of 3-5 were determined from their H-1 -NMR and circular dichroism (CD) spectra and by single-crystal X-ray d iffractometric analysis. The NE potentiating activity of the optically active 3-5 and previously prepared 3-methyl derivatives (3R,4R-6a and 3S,4S-6b) of PI-OH were tested. The results show that compounds 3, 4, and 6 had high enantioselectivity for NE potentiation: the 4R series of the enantiomers exhibited activity but not the 4S-enantiomers. The activity of the 4-desoxy compound 5 also resided exclusively in the 4S -enantiomer. These findings suggest the presence of a specific recepto r for NE uptake, and the enantiomers 3a, 4a, 5a, and 6a may be antagon istic at this NE uptake receptor.