1,3-dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the binding orientation of tetrahydroisoquinoline at the active site of phenylethanolamine N-methyltransferase

In order to determine the function of epinephrine (Epi) in the central nerv ous system, we have targeted the enzyme that catalyzes the final step in th e biosynthesis of Epi, phenylethanolamine N-methyltransferase (PNMT; EC 2.1 .1.28). 1,2,3,4-Tetrahydroisoquinolines (THIQs) are inhibitors of this enzy me, but also display affinity for the alpha(2)-adrenoceptor. To gain furthe r understanding about how THIQs bind at the PNMT active site and in an atte mpt to further increase the selectivity of THIQ-type inhibitors versus the alpha(2)-adrenoceptor, a series of cis- and trans-1,3-dimethyl-7-substitute d-THIQs were synthesized. Evaluation of these compounds suggests that THIQs bind in two different orientations at the PNMT active site, based on the l ipophilicity of the 7-substituent. However, no significant increases in sel ectivity versus the alpha(2)-adrenoceptor were observed for these compounds . (C) 1999 Elsevier Science Ltd. All rights reserved.