3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT Ki = 1.1 microM, alpha2 Ki = 6.6 microM, selectivity (alpha2 Ki/PNMT Ki) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its alpha2-adrenoceptor affinity, than is 3-methyl-1,2,3, 4-tetrahydroisoquinoline (2; PNMT Ki = 2.1 microM, alpha2 Ki = 0.76 microM, selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT Ki = 9.7 microM, alpha2 Ki = 0.35 microM, selectivity = 0. 036). Evaluation of the O-methyl ether derivative of 4 suggested that the 3-hydroxymethyl substituent might be involved in a hydrogen-bond donor-type of interaction at a sterically compact region in the PNMT active site. The directionality of the steric bulk tolerance at both the PNMT active site and the alpha2-adrenoceptor appears to be the same. Since the presence of a hydrophilic electron-withdrawing substituent (such as NO2, SO2CH3, or SO2NH2) at the 7-position of THIQ reduced the binding affinity toward the alpha2-adrenoceptor, we investigated the combination of both a hydrophilic electron-withdrawing 7-substituent and a 3-alkyl substituent on a THIQ nucleus. A synergistic effect in increasing the PNMT-inhibitory potency of the THIQ nucleus and reducing the affinity toward the alpha2-adrenoceptor was observed with this 3, 7-disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT Ki = 0.34 microM, alpha2 Ki = 1400 microM, selectivity = 4100) displayed a 23-680-fold enhanced selectivity over the parent compounds 27 (SK&F 29661; PNMT Ki = 0.55 microM, alpha2 Ki = 100 microM, selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.