Synthesis and evaluation of 3-substituted analogues of 1,2,3,4-tetrahydroisoquinoline as inhibitors of phenylethanolamine N-methyltransferase.
1,2,3,4-Tetrahydroisoquinoline (THIQ) and aryl-substituted derivatives of THIQ are potent inhibitors of the enzyme that catalyzes the formation of epinephrine--phenylethanolamine N-methyltransferase (PNMT, E.C. 2.1.1.28). In previous studies, we found that substitution of the 3-position of THIQ with a methyl group resulted in enhanced activity as an inhibitor for 3-methyl-THIQ with respect to THIQ itself. To more fully delineate this region of the PNMT active site, we have synthesized and evaluated other 3-substituted THIQ analogues that vary in both steric and electronic character. Extension of the methyl side chain in 8 by a single methylene unit results in diminished potency for 3-ethyl-THIQ, suggesting that this zone of the active site is spatially compact; furthermore, the region of steric intolerance may be located principally on only "one side" of the 3-position of bound THIQs, since the carbonyl containing (bent) analogues 3-(methoxycarbonyl)-THIQ and 3-(aminocarbonyl)-THIQ are much less capable of forming a strong enzyme-inhibitor dissociable complex compared to straight-chain derivatives possessing a similar steric component. The good activity of 3-(hydroxymethyl)-THIQ as a PNMT inhibitor cannot be explained solely by steric tolerance for this side chain. We believe that an active-site amino acid residue capable of specific (i.e., hydrogen bond) interactions is located in close proximity to the 3-position of bound THIQs and that association of the OH functionality with this active-site residue results in the enhanced in vitro potency of this analogue (Ki = 2.4 microM) compared to that of THIQ (Ki = 10.3 microM). Incorporation of a hydroxymethyl substituent onto the 3-position of the potent PNMT inhibitor 7,8-dichloro-THIQ (SKF 64139, Ki = 0.24 microM) did not result in the same enhancement in inhibitor potency for 17 (Ki = 0.38 microM). This result suggests that simultaneous binding in an optimal orientation of the aromatic halogens, secondary amine, and side-chain hydroxyl functionalities to the PNMT active site is not allowed in this analogue.
Grunewald
G L
GL
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
Sall
D J
DJ
Monn
J A
JA
D055598:Chemical Phenomena; D002621:Chemistry; D004837:Epinephrine / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology*; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine