Contribution of lateral substituents in heptane-bisammonium derivatives to the allosteric stabilization of antagonist binding to M2-receptors.
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.
Staudt
M
M
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Bonn, Germany.
Tränkle
C
C
Mohr
K
K
Holzgrabe
U
U
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
D006536:Heptanes; D018727:Muscarinic Antagonists; D000644:Quaternary Ammonium Compounds; D011976:Receptors, Muscarinic; D019832:N-Methylscopolamine