Grunewald G L, Sall D J, Monn J A
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
J Med Chem. 1988 Feb;31(2):433-44. doi: 10.1021/jm00397a029.
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.
苄胺（BA）类化合物是苯乙醇胺N-甲基转移酶（PNMT，EC 2.1.1.28）的强效抑制剂。将氨甲基侧链通过并入环状结构（如1,2,3,4-四氢异喹啉（THIQ）或2,3,4,5-四氢-1H-2-苯并氮杂䓬（THBA））来进行限制，会导致其作为抑制剂的效力增强，这表明BA与活性位点结合时存在构象效应；然而，这些环系统仍保留着高度的灵活性。我们合成了一系列苄胺的构象明确的类似物，以探究构象以及空间位阻对这类配体抑制PNMT的影响。此外，还合成了1-、3-和4-甲基取代的THIQ，并将其作为该环系统空间位阻耐受性的灵活模型进行评估。在THIQ的任一苄基位置上进行甲基取代，都会导致其作为PNMT抑制剂的活性降低；然而，3-甲基-THIQ作为抑制剂的活性相较于THIQ本身有所增强。类似物4-8中BA侧链的完全构象限制导致抑制剂效力急剧丧失。我们将这种效应归因于杂环系统上方（或下方）的烷基桥连单元与活性位点氨基酸残基之间的负空间相互作用。采用不在环系统上方（或下方）的桥连单元对THIQ进行构象限制，与THIQ本身相比，活性仅略有降低。根据构象描述符tau 1和tau 2对4-8的相对活性进行了研究。虽然tau 1与作为PNMT抑制剂的活性之间没有相关性，但tau 2（内型或外型）与PNMT活性之间的定性关系是明显的。我们认为，N-H和/或N上孤对电子的结合可能会影响这些分子在活性位点的空间取向，从而导致化合物4和8产生正结合相互作用，而类似物5-7产生负相互作用。将当前研究的结果与从一项涉及构象明确的苯丙胺的类似研究中获得的结果进行了比较。
