Stereochemical aspects of phenylethanolamine analogues as substrates of phenylethanolamine N-methyltransferase

Article abstract of DOI:10.1021/jm00118a021

Phenylethylamines and phenylethanolamines represent two major classes of ligands for the epinephrine synthesizing enzyme, phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). Phenylethylamines are usually competitive inhibitors and the isomers with the relative configuration as in (2S)-amphetamine and (2S)-2-aminotetralin are better inhibitors than their enantiomers. Phenylethanolamines are usually substrated of PNMT and the enzyme prefers the 1R isomers, such as (1R)-phenylethanolamine, in this class. Optically active norephedrines, norpseudoephedrines, and 2-amino-1-tetralols were used to study the stereochemical requirements of phenylethanolamines for PNMT active site binding. Although the norephedrines and the norpseudoephedrines were poorer ligands for PNMT than were the 2-amino-1-tetralols, (1R,2S)-(-)-norephedrine showed some activity as a pNMT substrate (K(m) = 1310 μM, V(max)/K(m) = 0.017). In the 2-amino-1-tetraols, the isomers with the 2S configuration showed higher affinity to PNMT (13, K(m) = 4.5 μM; 15, K(i) = 4.6 μM) and those with the 1R configuration were substrates for the PNMT-catalyzed methyl transfer (13, K(m) = 4.5 μM, V(max) = 0.16, 100 x V(max)/K(m) = 4.6; 16, K(m) = 195 μM, V(max) = 0.12, 100 x V(max)/K(m) = 0.062); the combination of 1R and 2S configurations, such as in (1R,2S)-2-amino-1-tetralol, was required for a good substrate. These stereochemical requirements derived from the norephedrines, the norpseudoephedrines, and the 2-amino-1-tetralols complement those for phenylethylamines and for phenylethanolamines and strongly suggest that phenylethylamine inhibitors bind to PNMT in the same orientation as do phenylethanolamine substrates.