Conformational and steric aspects of the inhibition of phenylethanolamine N-methyltransferase by benzylamines.
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.
Grunewald
G L
GL
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
Sall
D J
DJ
Monn
J A
JA
D001596:Benzylamines / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D007546:Isoquinolines / Q000494:pharmacology; D008968:Molecular Conformation; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
D001596:Benzylamines; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D010625:Phenylethanolamine N-Methyltransferase