| Abstract
| - 3-Hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (4) is a more selective inhibitor (PNMT Ki =1.1 μM, α2Ki = 6.6 μM, selectivity (α2Ki/PNMT Ki) = 6.0) of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), with respect to its α2-adrenoceptor affinity, than is3-methyl-1,2,3,4-tetrahydroisoquinoline (2; PNMT Ki = 2.1 μM, α2Ki = 0.76 μM, selectivity =0.36) or 1,2,3,4-tetrahydroisoquinoline (1, THIQ; PNMT Ki = 9.7 μM, α2Ki = 0.35 μM, selectivity= 0.036). Evaluation of the O-methyl ether derivative of 4 suggested that the 3-hydroxymethylsubstituent might be involved in a hydrogen-bond donor-type of interaction at a stericallycompact region in the PNMT active site. The directionality of the steric bulk tolerance at boththe PNMT active site and the α2-adrenoceptor appears to be the same. Since the presence ofa hydrophilic electron-withdrawing substituent (such as NO2, SO2CH3, or SO2NH2) at the7-position of THIQ reduced the binding affinity toward the α2-adrenoceptor, we investigatedthe combination of both a hydrophilic electron-withdrawing 7-substituent and a 3-alkylsubstituent on a THIQ nucleus. A synergistic effect in increasing the PNMT-inhibitory potencyof the THIQ nucleus and reducing the affinity toward the α2-adrenoceptor was observed withthis 3,7-disubstitution. Remarkably, 7-aminosulfonyl-3-hydroxymethyl-THIQ (12; PNMT Ki =0.34 μM, α2Ki = 1400 μM, selectivity = 4100) displayed a 23−680-fold enhanced selectivityover the parent compounds 27 (SK&F 29661; PNMT Ki = 0.55 μM, α2Ki = 100 μM, selectivity= 180) and 4 (selectivity = 6.0) and is thus the most selective PNMT inhibitor yet reported.
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