Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor
Gl. Grunewald et al., Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor, J MED CHEM, 42(21), 1999, pp. 4351-4361
An enantiospecific method was developed for the synthesis of 3-fluoromethyl
-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroiso
quinolines (THIQs) from phenylalanine. Biochemical evaluation of the enanti
omers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicat
es that both sites display similar stereoselectivity. Overall the R-enantio
mer was usually the more potent enantiomer at both PNMT and the alpha(2)-ad
renoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-
THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was fou
nd to display the opposite stereoselectivity at the alpha(2)-adrenoceptor.
A comparison of the PNMT inhibitory potency of the enantiomers of these 3-f
luoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all
of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT.
However, the nature of the 3-substituent was found to have a major effect o
n the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxym
ethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs conta
ining the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cya
no-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl (R-13
) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the
most selective inhibitors in this study and display selectivities (alpha 2
-adrenoceptor K-i/PNMT K-i) greater than 200. These compounds give importan
t insight into the steric and stereochemical preferences of both PNMT and t
he alpha(2)-adrenoceptor, which should assist in the: development of new PN
MT inhibitors.