Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, PO Box 9500, Morgantown, WV 26506, USA.
Eur Neuropsychopharmacol. 2013 Aug;23(8):960-71. doi: 10.1016/j.euroneuro.2012.08.005. Epub 2012 Aug 24.
Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity.
甲基苯丙胺是一种高度成瘾的精神兴奋剂药物滥用，在高剂量下会导致体温过高和神经毒性。目前，没有经过临床验证的药物治疗方法来治疗这些甲基苯丙胺的作用，因此需要确定潜在的新治疗靶点。早期的研究表明，甲基苯丙胺在生理相关浓度下与大脑中的西格玛（σ）受体结合，在那里它“部分作为激动剂起作用”。SN79（6-乙酰基-3-（4-（4-（4-氟苯基）哌嗪-1-基）丁基）苯并[d]恶唑-2（3H）-酮）被合成作为一种假定的σ受体拮抗剂，对σ受体具有纳摩尔亲和力和选择性，超过 57 个其他结合位点。SN79 预处理可防止雄性瑞士 Webster 小鼠因甲基苯丙胺引起的体温过高和纹状体多巴胺能和 5-羟色胺能神经毒性（通过纹状体多巴胺和 5-羟色胺水平的消耗以及纹状体多巴胺和 5-羟色胺转运蛋白表达水平的降低来衡量）。相比之下，二邻甲苯胍（DTG），一种成熟的 σ 受体激动剂，增加了甲基苯丙胺的致命作用，尽管它没有进一步加剧甲基苯丙胺引起的体温过高。总的来说，这些数据表明 σ 受体在直接调节甲基苯丙胺的一些作用方面具有重要作用，例如致死作用，同时还具有调节作用，可以减轻其他甲基苯丙胺引起的作用，如体温过高和神经毒性。
