Sullivan J P, Tipton K F
Department of Biochemistry, Trinity College, Dublin, Ireland.
J Neural Transm Suppl. 1990;29:269-77. doi: 10.1007/978-3-7091-9050-0_26.
The interactions of a number of derivatives of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with monoamine oxidase (MAO) have been studied. The desmethyl derivative, 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), was oxidised by MAO-B to form the corresponding dihydropyridine. Initial interaction with both forms of MAO was competitive. However the degree of inhibition of MAO-B, but not MAO-A, increased with time and became irreversible. Substitution of a methyl group at the 6-position of the heterocyclic ring of MPTP prevented it from acting as a substrate for MAO-B and greatly decreased its potency as an inhibitor of that form of MAO, although it remained a good competitive inhibitor of MAO-A. Replacement of the tetrahydropyridine ring of PTP by piperidine apparently abolished the ability to act as a substrate for MAO-B. The compound was however a competitive inhibitor of both forms of MAO. Substitution of a 3-(chlorophenyl)-methoxy-group at the 4'-position of this compound and PTP led to compounds which appeared to be devoid of substrate activity although they were potent, highly-selective, time-dependent inhibitors of MAO-B.
已对多巴胺能神经毒素MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）的多种衍生物与单胺氧化酶（MAO）的相互作用进行了研究。去甲基衍生物4-苯基-1,2,3,6-四氢吡啶（PTP）被MAO-B氧化形成相应的二氢吡啶。与两种形式的MAO的初始相互作用都是竞争性的。然而，MAO-B的抑制程度随时间增加且变得不可逆，而MAO-A则不然。在MPTP杂环的6位取代甲基可阻止其作为MAO-B的底物，并大大降低其作为该形式MAO抑制剂的效力，尽管它仍然是MAO-A的良好竞争性抑制剂。用哌啶取代PTP的四氢吡啶环显然消除了其作为MAO-B底物的能力。然而，该化合物是两种形式MAO的竞争性抑制剂。在该化合物和PTP的4'-位取代3-（氯苯基）-甲氧基，得到的化合物似乎没有底物活性，尽管它们是MAO-B的强效、高选择性、时间依赖性抑制剂。
