3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline inhibitors of phenylethanolamine N-methyltransferase that display remarkable potency and selectivity.

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