PMID: 9180353Jan 1, 1997Paper

Molecular rigidity and potency of bispyridinium type allosteric modulators at muscarinic M2-receptors

Life Sciences
C TränkleK Mohr

Abstract

Several bispyridinium compounds have been shown to be potent allosteric modulators of ligand binding to muscarinic M2-receptors. ,,Uno compounds" are benzyl derivatives of the bispyridinium "TMB4" (trimethylene-bis-[4-hydroxy-iminomethyl-pyridinium]). To gain more insight into structure activity relationships, eleven derivatives with varying structure of the oxime-linked aromatic substituent were tested for their ability to inhibit the equilibrium-binding of [3H]N-methylscopolamine ([3H]NMS) in guinea pig cardiac membranes and to retard [3H]NMS-dissociation allosterically. At a concentration of 3 microM, all compounds reduced [3H]NMS-binding to about 40 % of the control level, indicating a similar potency to inhibit the association of [3H]NMS. Allosteric retardation of [3H]NMS-dissociation required higher concentrations. Comparing the effects of the compounds at 30 and 300 microM, respectively, revealed considerable differences in potency. Therefore, the concentration-dependency of the delay of [3H]NMS-dissociation was determined for selected compounds. The results indicate that introduction of a benzyl-moiety into TMB4 leads to a 20-fold increase in allosteric potency. A further increment by a factor of 10 is obtained with the...Continue Reading

References

Feb 15, 1992·American Journal of Medical Genetics·A M NormanD Donnai
Oct 24, 1991·Biochemical Pharmacology·J EllisM R Brann
Jul 5, 1991·Biochemical Pharmacology·N H Lee, E E el-Fakahany
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Citations

Jan 20, 2010·The Journal of Biological Chemistry·Monika Maier-PeuschelMartin J Lohse
May 20, 1998·Clinical and Experimental Pharmacology & Physiology·A ChristopoulosF Mitchelson
Apr 6, 2001·European Journal of Pharmacology·A LanzafameF Mitchelson
May 3, 2003·Pharmacology & Therapeutics·Chris J van Koppen, Björn Kaiser
Mar 5, 2004·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Anders A Jensen, Tracy A Spalding
May 20, 2006·Molecular Pharmacology·Alfred A LanzafameArthur Christopoulos

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