Rojas Asheebo, Ganesh Thota, Walker Alec, Dingledine Raymond
Department of Pharmacology, Emory University , 1510 Clifton Road NE, Atlanta, Georgia 30322, United States.
ACS Chem Neurosci. 2017 Apr 19;8(4):712-717. doi: 10.1021/acschemneuro.6b00334. Epub 2017 Jan 6.
Quaternary ammonium analogues of atropine that are unable to cross the blood-brain barrier are used to alleviate peripheral muscarinic toxicity in animal models of epilepsy produced by systemic administration of pilocarpine or diisopropylfluorophosphate (DFP). Currently, methylatropine is the most popular and potent of these quaternary derivatives; however, it is expensive and produced in limited quantity. Here, we propose the use of ethylatropine bromide as an alternative to methylatropine. The synthesis of ethylatropine bromide is simple, inexpensive and has low environmental impact. We demonstrate the efficacy of ethylatropine bromide to antagonize the carbachol induced rise in intracellular calcium in a calcium mobilization assay, and its ability to prevent pilocarpine-induced total fluid secretions in mice without blocking pilocarpine-induced seizures. The ease of synthesis, cost effectiveness, and efficacy makes ethylatropine bromide a desirable alternative to methylatropine as a peripherally restricted acetylcholine receptor antagonist.
无法穿过血脑屏障的阿托品季铵类似物被用于减轻在通过全身给予毛果芸香碱或二异丙基氟磷酸酯（DFP）产生的癫痫动物模型中的外周毒蕈碱毒性。目前，甲基阿托品是这些季铵衍生物中最常用且效力最强的；然而，它价格昂贵且产量有限。在此，我们提议使用溴化乙基阿托品作为甲基阿托品的替代品。溴化乙基阿托品的合成简单、成本低且对环境影响小。我们在钙动员试验中证明了溴化乙基阿托品拮抗卡巴胆碱诱导的细胞内钙升高的功效，以及其在不阻断毛果芸香碱诱导的癫痫发作的情况下预防小鼠毛果芸香碱诱导的总液体分泌的能力。合成的简便性、成本效益和功效使溴化乙基阿托品成为作为外周限制型乙酰胆碱受体拮抗剂的甲基阿托品的理想替代品。
