Synthesis and evaluation of 3-trifluoromethyl-7-substituted-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.
A series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the alpha(2)-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the alpha(2)-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the alpha(2)-adrenoceptor and to the decreased pK(a) of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT K(i) = 0.52 microM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity alpha(2) K(i)/PNMT K(i) = 700; 16, selectivity alpha(2) K(i)/PNMT K(i) > 1900). Compounds 14 and 16 are also quite lipophilic due to the 3-trifluoromethyl moiety and represent promising new leads for the development of new highly selective inhibitors of PNMT, which should be sufficiently lipophilic to penetrate the blood-brain barrier.
Grunewald
G L
GL
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ukans.edu
Caldwell
T M
TM
Li
Q
Q
Criscione
K R
KR
D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D003000:Clonidine / 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; D008297:Male; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
C121212:3-trifluoromethyl-7-bromo-1,2,3,4-tetrahydroisoquinoline; C121211:3-trifluoromethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018341:Receptors, Adrenergic, alpha-2; D044005:Tetrahydroisoquinolines; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine