3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines display remarkable potency and selectivity as inhibitors of phenylethanolamine N-methyltransferase versus the α2-adrenoceptor

3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT K-i = 1.1 mu M, alpha(2) K-i = 6.6 mu M, selectivity (alpha(2) K-i/PNMT K-i) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its az-adrenoceptor affinity, than is 3-methyl-1,2,3,4-tetrahydroisoquinoline (2; PNMT K-i = 2.1 mu M, alpha 2 K-i = 0.76 mu M, selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT K-i = 9.7 mu M, alpha 2 K-i = 0.35 mu M, 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 alpha(2)-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 alpha(2)-adrenoceptor, we investigated the combination of both a hydrophilic electron-withdrawing 7-substituent and a S-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 alpha(2)-adrenoceptor was observed with this 3,7-disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT K-i = 0.34 mu M, alpha 2 K-i = 1400 mu M, selectivity = 4100) displayed a 23-680-fold enhanced selectivity over the parent compounds 27 (SK&F 29661; PNMT K-i = 0.55 mu M, alpha 2 K-i = 100 mu M, selectivity = 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.