252659-50-0Relevant articles and documents
Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3- chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the α2-adrenoceptor
Grunewald, Gary L.,Caldwell, Timothy M.,Li, Qifang,Dahanukar, Vilas H.,McNeil, Brynn,Criscione, Kevin R.
, p. 4351 - 4361 (1999)
An enantiospecific method was developed for the synthesis of 3- fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4- tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the α2-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R- enantiomer was usually the more potent enantiomer at both PNMT and the α2- adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl- THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the α2-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3- fluoromethyl-, 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 on the α2-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R- 12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (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 (α2- adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the α2-adrenoceptor, which should assist in the development of new PNMT inhibitors.
