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Pharmacology and Toxicology, Institute of Pharmacy, University of
Bonn, 53121 Bonn, Germany
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° (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.
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