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

Abstract

3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT K(i) = 1.1 μM, α2 K(i) = 6.6 μM, selectivity (α2 K(i)/PNMT K(i)) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its α2-adrenoceptor affinity, than is 3-methyl- 1,2,3,4-tetrahydroisoquinoline (2; PNMT K(i) = 2.1μM, α2 K(i) = 0.76 μM, selectivity = 0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT K(i) = 9.7 μM, α2 K(i) = 0.35 μM, 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 α2-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 α2-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 α2-adrenoceptor was observed with this 3,7- disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT K(i) = 0.34 μM, α2 K(i) = 1400 μM, selectivity = 4100) displayed a 23- 680-fold enhanced selectivity over the parent compounds 27 (SK and F 29661; PNMT K(i) = 0.55 μM, α2 K(i) = 100 μM, selectivity = 180) and 4 selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.