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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Divergent modes of action among cationic allosteric modulators of muscarinic M2 receptors.

We tested the hypothesis that structurally related modulators of ligand binding to muscarinic M2 receptors may not use a common recognition site. The applied test compounds are potent allosteric modulators [i.e., two bispyridinium model compounds substituted symmetrically either with phthalimidomethyl (WDuo3) or dichlorobenzyl (Duo3), a phthalimidoethyl-substituted hexamethonium compound (W84), alcuronium, and, for sake of comparison, gallamine]. As introduced by Ellis and Seidenberg as a tool to check for a common allosteric site [Mol. Pharmacol. 42:638-641 (1992)], obidoxime was used to antagonize the actions of the test compounds. The allosteric delay of the dissociation of [3H]N-methylscopolamine ([3H]NMS) from porcine heart muscarinic receptors was measured in 5 mM sodium/potassium phosphate buffer (4 mM Na2HPO4 and 1 mM KH2PO4, pH 7.4) at 23 degrees (control t1/2 = 4 min). The concentration-effect curve of obidoxime, which has a weak potency and submaximal efficacy to allosterically retard [3H]NMS dissociation, was better described with a two-site model than with a one-site model. The concentration-effect curves of the test compounds for the allosteric delay of [3H]NMS dissociation were shifted to the right in the presence of obidoxime, yet to a different extent. For WDuo3, W84, alcuronium, and gallamine, the shift induced by increasing concentrations of obidoxime was compatible with a competitive interplay. The pKb values of obidoxime against these modulators lay in a narrow range from pKb = 4.70 with gallamine to pKb = 4.16 with WDuo3. In contrast, the ability of obidoxime to shift the concentration-effect curve of Duo3 was weak (pA2 = 3.00) and not compatible with a competitive interplay. In conclusion, cationic allosteric modulators may stabilize [3H]NMS binding to M2 receptors by divergent modes of allosteric action. The findings suggest that the M2 receptor protein contains more than one allosteric recognition site on its extracellular face.[1]

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