Synthesis and Enantioselectivity of Optically Active 1- and 3-Substituted 4-Phenyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ols and Related Compounds as Norepinephrine Potentiators

Abstract

Optically active 1, 2-dimethyl-4-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ols (1R, 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 2-methyl-4-phenyl-1, 2, 3, 4-tetrahydroisoquinolin-4-ol (PI-OH) (1) on the enantioselectivity for norepinephrine (NE) potentiating activity. The conformations and absolute configurations of 3-5 were determined from their ¹H-NMR and circular dichroism (CD) spectra and by single-crystal X-ray diffractometric 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 receptor for NE uptake, and the enantiomers 3a, 4a, 5a, and 6a may be antagonistic at this NE uptake receptor.