Grunewald Gary L, Romero F Anthony, Criscione Kevin R
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
J Med Chem. 2005 Jan 13;48(1):134-40. doi: 10.1021/jm049368n.
Six 3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (16-21) were synthesized and evaluated for their phenylethanolamine N-methyltransferase (PNMT) inhibitory potency and affinity for the alpha(2)-adrenoceptor. The addition of nonpolar substituents to the sulfonamide nitrogen of 9 (3-CH(2)OH-7-SO(2)NH(2)-THIQ) led to inhibitors (16-21) that have high PNMT inhibitory potency and high selectivity, and most of these (16-21) are predicted, on the basis of their calculated log P values, to be able to penetrate the blood-brain barrier. Compounds N-trifluoroethyl sulfonamide 20 (PNMT K(i) = 23 nM) and N-trifluoropropyl sulfonamide 21 (PNMT K(i) = 28 nM) are twice as potent at inhibiting PNMT compared to 9 and display excellent selectivity (alpha(2) K(i)/PNMT K(i) > or = 15,000).
合成了六种3-羟甲基-7-(N-取代氨磺酰基)-1,2,3,4-四氢异喹啉(16 - 21)，并对它们抑制苯乙醇胺N-甲基转移酶(PNMT)的效力以及对α₂-肾上腺素能受体的亲和力进行了评估。在9(3-CH₂OH - 7-SO₂NH₂-THIQ)的磺酰胺氮上添加非极性取代基，得到了具有高PNMT抑制效力和高选择性的抑制剂(16 - 21)，并且根据它们计算得到的log P值预测，其中大多数(16 - 21)能够穿透血脑屏障。化合物N-三氟乙基磺酰胺20(PNMT Kᵢ = 23 nM)和N-三氟丙基磺酰胺21(PNMT Kᵢ = 28 nM)抑制PNMT的效力是9的两倍，并且表现出优异的选择性(α₂ Kᵢ/PNMT Kᵢ≥15,000)。
