Inhibition of phenylethanolamine n-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4-tetrahydroisoquinolines: Further studies on the hydrophilic pocket of the aromatic ring binding region of the active site

Article abstract of DOI:10.1021/jm00395a006

In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound β-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound β-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.