Abstract

beta-Phenylethanolamines have long been known to be substrates for the enzyme that converts norepinephrine to epinephrine (phenylethanolamine N-methyltransferase, PNMT, EC 2.1.1.28). In an effort to determine which, if any, particular conformation of the aminoethyl side chain of phenylethanolamines is required for PNMT active site binding and catalysis, we have prepared and evaluated conformationally restricted phenylethanolamine analogues 8-10. The folded phenylethanolamine derivative 4-hydroxy-1,2,3,4-tetrahydroisoquinoline (8) is not a substrate and does not interact with the enzyme active site as an inhibitor as well as 1,2,3,4-tetrahydroisoquinoline (6). In the cyclic 2-aminotetralol systems, only cis-phenylethanolamine derivative 9 demonstrates activity as a PNMT substrate. The corresponding trans isomer 10 is not a substrate, in spite of enhanced active site interactions with respect to the parent analogue (2-aminotetralin, 4). Comparison of the inhibition constants for the folded (8,Ki = 175 microM) and extended (10,Ki = 9 microM) phenylethanolamine analogues strongly suggests that simultaneous binding of both the amino and hydroxyl functionalities to the PNMT active site requires an extended aminoethyl side chain conformation.