Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
School of Mathematical and Physical Sciences, Faculty of Science , The University of Technology Sydney , Sydney , NSW 2007 , Australia.
J Med Chem. 2019 Mar 14;62(5):2466-2484. doi: 10.1021/acs.jmedchem.8b01775. Epub 2019 Feb 20.
Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).
靶向甘氨酸转运蛋白 2（GlyT2）的抑制剂有望成为镇痛药，但由于完全或不可逆结合，可能会受到毒性的限制。酰基-甘氨酸抑制剂对 GlyT2 具有选择性，并已在疼痛动物模型中显示出具有最小副作用的镇痛作用，但它们是相对较弱的 GlyT2 抑制剂。在这里，我们通过合成一系列具有 l-和 d-构型的各种氨基酸头基的脂类类似物来修饰简单的酰基-甘氨酸，从而产生具有纳摩尔亲和力的、选择性的 GlyT2 抑制剂。强效抑制剂油酰基-d-赖氨酸（33）在人和大鼠血浆以及肝微粒体中也不易降解，并且在大鼠腹腔注射后迅速被吸收，并容易穿过血脑屏障。我们证明，33 以较低剂量提供更大的镇痛作用，并且没有非常缓慢可逆的 GlyT2 抑制剂 ORG25543（2）的严重副作用。
