title: Contribution of lateral substituents in heptane-bisammonium derivatives to the allosteric stabilization of antagonist binding to M2-receptors.
abstract: Phthalimide-containing heptane-bisammonium-type compounds retard the dissociation of the antagonist [3H]-N-methylscopolamine ([3H]NMS) from muscarinic M2-receptor allosterically with high potency. To study the contribution of the lateral substituents to this effect, a series of derivatives was synthesized in which the phthalimide moiety was truncated. The potency of the compounds to delay [3H]NMS dissociation was measured in porcine heart homogenates (50 mM Tris-HCl, 3 mM MgHPO4, pH 7.3, 37 degrees C). Potency declined with diminuition of the lateral substituents, e.g. loss of the aromatic ring of the phthalimide resulted in a 400fold reduction in potency. In the hexahydrophthalimide derivatives, the cis-stereoisomer was about fivefold more potent than the trans-isomer. In conclusion, almost flat hydrophobic lateral moieties appear to be pivotal for high allosteric potency, suggesting a hydrophobic interaction of these parts of the molecule with the [3H]NMS occupied receptor protein.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Staudt
authors.forename: C
authors.initials: C
authors.lastname: Tränkle
authors.forename: K
authors.initials: K
authors.lastname: Mohr
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D006536:Heptanes / Q000494:pharmacology*; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D019832:N-Methylscopolamine / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D006536:Heptanes; D018727:Muscarinic Antagonists; D000644:Quaternary Ammonium Compounds; D011976:Receptors, Muscarinic; D019832:N-Methylscopolamine