Structure−Activity Relationships in a Series of Bisquaternary Bisphthalimidine Derivatives Modulating the Muscarinic M2-Receptor Allosterically

• Published in: Journal of medicinal chemistry Vol. 43; no. 11; pp. 2155 - 2164
• Main Authors: Botero Cid, Hector M, Tränkle, Christian, Baumann, Knut, Pick, Rainer, Mies-Klomfass, Elisabeth, Kostenis, Evi, Mohr, Klaus, Holzgrabe, Ulrike
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.06.2000
• Subjects: Biological and medical sciences; Cholinergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Heart; Nitrogen heterocycle; Ligand; Lactam; Modeling; Cholinergic receptor; Structure activity relation; Molecular model; Bicyclic compound; Aromatic compound; Chemical synthesis; Ungulata; In vitro; Pig; Quaternary ammonium compound; Vertebrata; Biological fixation; Mammalia; Non depolarisant myorelaxant; Allosteric regulation; Animal; M2 Muscarinic receptor; Affinity; Artiodactyla; Organic dication
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991136e

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are well-established ligands of the common allosteric binding site of muscarinic M2 receptors. Previous structure−activity relationships (SAR) revealed two positively charged centers and two lateral phthalimide moieties in a defined arrangement to be essential of a high allosteric potency. The purpose of this study was to replace one carbonyl group of the phthalimides with hydrogens, hydroxy, alkoxy, phenyl, benzyl, and benzylidene groups in order to check the influence of these substituents on the allosteric activity in antagonist-linked receptors. The analysis of the quantitative SAR indicated that a high allosteric potency is related to a certain amount of rigidity as well as polarizibility and the ability to form hydrophobic interactions.