Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
J Med Chem. 2020 Mar 12;63(5):2343-2357. doi: 10.1021/acs.jmedchem.9b01188. Epub 2019 Nov 14.
Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol () was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ receptors. Within the series, showed improved DAT affinity ( = 23 nM) over ( = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of as a potential treatment for psychostimulant use disorders.
非典型多巴胺转运体 (DAT) 抑制剂在精神兴奋剂滥用的临床前模型中显示出治疗潜力。在大鼠中，1-(4-(2-((双(4-氟苯基)甲砜基)乙基)哌嗪-1-基)-1-丙醇 () 有效降低可卡因和甲基苯丙胺的强化作用，但本身没有表现出精神兴奋剂行为。虽然 的进一步开发正在进行中，但对映体分离以及提高效力和药代动力学是发现药物候选物的理想选择。因此，设计、合成并评估了一系列双(4-氟苯基)甲砜基)烷基脂环族胺，其中哌嗪-2-丙醇支架被修饰，以评估它们在 DAT 以及 5-羟色胺转运体和 σ 受体上的结合亲和力。在该系列中， 对 DAT 的亲和力（ = 23 nM）优于 （ = 230 nM），在人肝微粒体中具有中等代谢稳定性，hERG/DAT 亲和力比 = 28。虽然 与载体相比增加了运动活性，但明显低于可卡因产生的活性。这些结果支持进一步研究 作为治疗精神兴奋剂使用障碍的潜在药物。
