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Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor
ChemMedChem ( IF 3.6 ) Pub Date : 2018-11-27 , DOI: 10.1002/cmdc.201800539 Sebastian Rappenglück 1 , Sonja Sichler 1 , Georg Höfner 1 , Thomas Wein 1 , Karin V. Niessen 2 , Thomas Seeger 2 , Franz F. Paintner 1 , Franz Worek 2 , Horst Thiermann 2 , Klaus T. Wanner 1
ChemMedChem ( IF 3.6 ) Pub Date : 2018-11-27 , DOI: 10.1002/cmdc.201800539 Sebastian Rappenglück 1 , Sonja Sichler 1 , Georg Höfner 1 , Thomas Wein 1 , Karin V. Niessen 2 , Thomas Seeger 2 , Franz F. Paintner 1 , Franz Worek 2 , Horst Thiermann 2 , Klaus T. Wanner 1
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The current standard therapy to counteract organophosphate intoxication is not effective in equal measure against all types of organophosphorus compounds (OPCs), as the outcome of oxime‐induced reactivation of inactivated acetylcholinesterase (AChE) strongly depends on the particular OPC. In case the reactivation is insufficient, acetylcholine concentrations that rise to pathophysiological levels force the nicotinic acetylcholine receptor (nAChR) into a desensitized state and hence a functionally inactive state. As a consequence, neurotransmission is irreversibly disrupted at the neuromuscular junction. Previous electrophysiological studies identified the symmetric bispyridinium compound 1,1′‐(propane‐1,3‐diyl)bis[4‐(tert‐butyl)pyridin‐1‐ium] diiodide (MB327) as a re‐sensitizer of the desensitized nAChR. MB327 is thereby capable of restoring the functional activity. Very recently, in silico modeling studies suggested non‐symmetric derivatives of MB327 as potential re‐sensitizers with enhanced binding affinity and thus possible enhanced efficacy. In this study, 26 novel non‐symmetric bispyridinium compounds and related derivatives were synthesized. For the synthesis of the highly polar target compounds in sufficient quantities, newly developed and highly efficient two‐step procedures were used. Compounds were characterized in terms of their binding affinity toward the MB327 binding site at the nAChR using recently developed mass spectrometry (MS) Binding Assays. Regarding structure–affinity relationships at the MB327 binding site, the presence of two quaternary aromatic nitrogen centers as well as pyridinium systems with a tert‐butyl group at the 4‐position or a NMe2 group at the 3‐ or 4‐positions appeared to be beneficial for high binding affinities.
中文翻译：
一系列非对称联吡啶鎓及其相关化合物的合成及其在烟碱乙酰胆碱受体上的亲和特征
目前用于抵消有机磷酸盐中毒的标准疗法在所有类型的有机磷化合物（OPC）上均不能有效地解决，因为肟诱导的灭活乙酰胆碱酯酶（AChE）活化的结果在很大程度上取决于特定的OPC。如果再活化不足，则升高到病理生理水平的乙酰胆碱浓度会迫使烟碱乙酰胆碱受体（nAChR）进入脱敏状态，从而进入功能失活状态。结果，在神经肌肉接头处神经传递被不可逆地破坏。先前的电生理研究确定了对称的双吡啶鎓化合物1,1'-（丙烷-1,3-二基）bis [4-（叔）-丁基）吡啶-1-鎓二碘化物（MB327）作为脱敏nAChR的再敏化剂。MB327从而能够恢复功能活性。最近，计算机模拟研究表明，MB327的非对称衍生物可作为潜在的增敏剂，具有增强的结合亲和力，因此可能具有增强的功效。在这项研究中，合成了26种新颖的非对称双吡啶鎓化合物及其相关衍生物。为了合成足够数量的高极性目标化合物，使用了新开发的高效两步程序。使用最近开发的质谱（MS）结合测定法，根据其对nAChR处MB327结合位点的结合亲和力来表征化合物。关于MB327结合位点的结构亲和力关系，在4位的叔丁基或在3位或4位的NMe 2基团似乎有利于高结合亲和力。
更新日期：2018-11-27
中文翻译：
一系列非对称联吡啶鎓及其相关化合物的合成及其在烟碱乙酰胆碱受体上的亲和特征
目前用于抵消有机磷酸盐中毒的标准疗法在所有类型的有机磷化合物（OPC）上均不能有效地解决，因为肟诱导的灭活乙酰胆碱酯酶（AChE）活化的结果在很大程度上取决于特定的OPC。如果再活化不足，则升高到病理生理水平的乙酰胆碱浓度会迫使烟碱乙酰胆碱受体（nAChR）进入脱敏状态，从而进入功能失活状态。结果，在神经肌肉接头处神经传递被不可逆地破坏。先前的电生理研究确定了对称的双吡啶鎓化合物1,1'-（丙烷-1,3-二基）bis [4-（叔）-丁基）吡啶-1-鎓二碘化物（MB327）作为脱敏nAChR的再敏化剂。MB327从而能够恢复功能活性。最近，计算机模拟研究表明，MB327的非对称衍生物可作为潜在的增敏剂，具有增强的结合亲和力，因此可能具有增强的功效。在这项研究中，合成了26种新颖的非对称双吡啶鎓化合物及其相关衍生物。为了合成足够数量的高极性目标化合物，使用了新开发的高效两步程序。使用最近开发的质谱（MS）结合测定法，根据其对nAChR处MB327结合位点的结合亲和力来表征化合物。关于MB327结合位点的结构亲和力关系，在4位的叔丁基或在3位或4位的NMe 2基团似乎有利于高结合亲和力。
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