3-Hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline Inhibitors of Phenylethanolamine N-Methyltransferase that Display Remarkable Potency and Selectivity<SUP>1</SUP>

Six 3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (<BO>16</BO><BO>−</BO><BO>21</BO>) were synthesized and evaluated for their phenylethanolamine N-methyltransferase (PNMT) inhibitory potency and affinity for the α<INF>2</INF>-adrenoceptor. The addition of nonpolar substituents to the sulfonamide nitrogen of <BO>9</BO> (3-CH<INF>2</INF>OH-7-SO<INF>2</INF>NH<INF>2</INF>-THIQ) led to inhibitors (<BO>16</BO><BO>−</BO><BO>21</BO>) that have high PNMT inhibitory potency and high selectivity, and most of these (<BO>16</BO><BO>−</BO><BO>21</BO>) are predicted, on the basis of their calculated log P values, to be able to penetrate the blood−brain barrier. Compounds N-trifluoroethyl sulfonamide <BO>20</BO> (PNMT K<INF>i</INF> = 23 nM) and N-trifluoropropyl sulfonamide <BO>21</BO> (PNMT K<INF>i</INF> = 28 nM) are twice as potent at inhibiting PNMT compared to <BO>9</BO> and display excellent selectivity (α<INF>2</INF> K<INF>i</INF>/PNMT K<INF>i</INF> ≥ 15 000).