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

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 d...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2000-06, Vol.43 (11), p.2155-2164
Main Authors: Botero Cid, Hector M, Tränkle, Christian, Baumann, Knut, Pick, Rainer, Mies-Klomfass, Elisabeth, Kostenis, Evi, Mohr, Klaus, Holzgrabe, Ulrike
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cholinergic system
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm991136e