Miller David J, Bashir-Uddin Surfraz M, Akhtar Mahmoud, Gani David, Allemann Rudolf K
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, UK B15 2TT.
Org Biomol Chem. 2004 Mar 7;2(5):671-88. doi: 10.1039/b312808c. Epub 2004 Feb 5.
Inositol monophosphatase is widely held to be the therapeutic target for inhibition by lithium ion in the treatment of bipolar disorder. In a continued effort to improve the bioavailability of alternative inhibitors, we have designed and tested two new series of compounds; phosphonates and product-like mimics. Phosphonate substrate mimics were competitive inhibitors of reduced potency as compared to phosphate based inhibitors. Product mimics however, showed various inhibitory modes of action. The 6-butylamino derivative 6p was an uncompetitive inhibitor when acting alone (K(i)= 0.3 mM) but displayed non-competitive inhibition in the presence of inorganic phosphate. This compound represents a new lead in the search for a viable replacement for lithium ion therapy.
肌醇单磷酸酶被广泛认为是锂离子在双相情感障碍治疗中发挥抑制作用的治疗靶点。为了持续努力提高替代抑制剂的生物利用度，我们设计并测试了两个新的化合物系列；膦酸盐和产物类似物模拟物。与基于磷酸盐的抑制剂相比，膦酸盐底物模拟物是效力降低的竞争性抑制剂。然而，产物模拟物显示出各种抑制作用模式。6-丁基氨基衍生物6p单独作用时是一种非竞争性抑制剂（K(i)= 0.3 mM），但在无机磷酸盐存在下表现出非竞争性抑制作用。该化合物代表了寻找锂离子疗法可行替代物的新线索。
