6H,13H-Pyrazino[1,2-a;4,5-a′]diindole analogs: Probing the pharmacophore for allosteric ligands of muscarinic M₂ receptors

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• 作者：Darius P. Zlotos ; Christian Trä ; nkle ; Aliaa Abdelrahman ; Daniela Gü ; ndisch ; Krzysztof Radacki ; Holger Braunschweig and Klaus Mohr
• 关键词：Muscarinic M₂ receptors ; Allosteric ligands
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 March 2006
• 卷：16
• 期：6
• 页码：1481-1485
• 文件大小：227 K

摘要

A series of 6H,13H-pyrazino[1,2-a;4,5-a′]diindole analogs was synthesized in order to probe the pharmacophore hypothesis for allosteric ligands of muscarinic M₂ receptors. The 3D structure of the novel ring system was determined by means of NMR spectroscopy and X-ray diffraction revealing a totally flat geometry. Low binding affinities for the [³H]N-methylscopolamine-occupied M₂ receptors (reflected by EC_50,diss) indicated that the spatial arrangement of the pharmacophore elements (two aromatic rings flanked by two cationic centers) incorporated in the bisquaternary analogs 5 and 6 is unfavorable for strong ligand–receptor interactions. Due to the structural similarity of the novel compounds to neuromuscular-blocking agents, their affinities (reflected by K_i) to the muscle type of nicotinic acetylcholine receptors were also determined. The dimethyl and diallyl analogs 5 and 6 exhibited rather high affinities to the muscle type of nicotinic acetylcholine receptors, suggesting a pronounced neuromuscular-blocking activity. Compound 5 showed a 34-fold higher affinity for the muscle type nAChR than for the allosteric site of M₂ receptors.