6H,13H-Pyrazino[1,2-a; 4,5-a']diindole analogs: Probing the pharmacophore for allosteric ligands of muscarinic M sub(2) receptors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 6; pp. 1481 - 1485
• Main Authors: Zlotos, Darius P, Traenkle, Christian, Abdelrahman, Aliaa, Guendisch, Daniela, Radacki, Krzysztof, Braunschweig, Holger, Mohr, Klaus
• Format: Journal Article
• Language: English
• Published: 01.01.2006
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.12.030

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 M sub(2) 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 [ super(3)H]N-methylscopolamine-occupied M sub(2) receptors (reflected by EC sub(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 sub(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 M sub(2) receptors.