3-methyl-1-2-3-4-tetrahydroisoquinoline and 1-2-3-4-tetrahydroisoquinoline

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.

Topics: Chemical Phenomena; Chemistry; Epinephrine; Isoquinolines; Phenylethanolamine N-Methyltransferase; Structure-Activity Relationship; Tetrahydroisoquinolines

Compounds of the benzylamine (BA) class are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). Restriction of the aminomethyl side chain through its incorporation into a cyclic framework as in 1,2,3,4-tetrahydroisoquinoline (THIQ) or 2,3,4,5-tetrahydro-1H-2-benzazepine (THBA) results in enhanced potency as an inhibitor, suggesting a conformational effect in the binding of BAs to the active site; however, these ring systems still retain a high degree of flexibility. We have synthesized a series of conformationally defined analogues of benzylamine in order to probe the effect of conformation, as well as the influence of steric bulk, on PNMT inhibition by this class of ligands. In addition, 1-, 3-, and 4-methyl-substituted THIQs were synthesized and evaluated as flexible models for steric bulk tolerance about this ring system. Substitution by a methyl group on either benzylic position of THIQ results in diminished activity as a PNMT inhibitor; however, 3-methyl-THIQ shows enhanced activity as an inhibitor vs THIQ itself. Full conformational restriction of the BA side chain in analogues 4-8 results in a dramatic loss in inhibitor potency. We attribute this effect to a negative steric interaction between the alkyl bridging units above (or below) the heterocyclic ring systems and an active-site amino acid residue. Conformational restriction of THIQ employing a bridging unit that is not located above (or below) the ring system results in only slightly diminished activity compared to THIQ itself. The relative activities of 4-8 were examined in terms of the conformational descriptors tau 1 and tau 2. Although there is no correlation between tau 1 and activity as a PNMT inhibitor, a qualitative relationship between tau 2 (endo or exo) and activity with PNMT is apparent. We believe that the binding of the N-H and/or N-lone pair of electrons may influence the spatial orientation of these molecules at the active site, resulting in positive binding interactions for compounds 4 and 8 and negative interactions for analogues 5-7. The results from the current investigation are compared to those obtained from a similar study involving conformationally defined amphetamines.

Topics: Benzylamines; Binding Sites; Isoquinolines; Molecular Conformation; Phenylethanolamine N-Methyltransferase; Structure-Activity Relationship; Tetrahydroisoquinolines