3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines display remarkable potency and selectivity as inhibitors of phenylethanolamine N-methyltransferase versus the alpha2-adrenoceptor.
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.
Grunewald
G L
GL
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ukans.edu
Dahanukar
V H
VH
Teoh
B
B
Criscione
K R
KR
D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D044005:Tetrahydroisoquinolines
C119478:7-aminosulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D010625:Phenylethanolamine N-Methyltransferase