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Vol. 53, Issue 6, 1120-1130, June 1998
Division of Neuroscience Research in Psychiatry (A.C., J.L.S.,
E.E.E.) and
Department of Cell Biology and Neuroanatomy (T.L.P.),
University of Minnesota Medical School, Minneapolis, Minnesota 55455
We investigated the molecular nature of the interaction between the
functionally selective M1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline and the human M1 mAChR expressed
in Chinese hamster ovary (CHO) cells. In contrast to the
non-subtype-selective agonist carbachol, xanomeline demonstrated
M1 mAChR binding that was resistant to extensive washout,
resulting in a significant reduction in apparent
N-[3H]methylscopolamine saturation binding
affinity in intact cells. Functional assays, using both M1
mAChR-mediated phosphoinositide hydrolysis and activation of neuronal
nitric oxide synthase, confirmed that this persistent binding resulted
in elevated basal levels of system activity. Furthermore, this
phenomenon could be reversed by the addition of the antagonist
atropine. However, pharmacological analysis of the inhibition by
atropine of xanomeline-mediated functional responses indicated a
possible element of noncompetitive behavior that was not evident in
several kinetic and equilibrium binding experimental paradigms. Taken
together, our findings indicate for the first time a novel mode of
interaction between an mAChR agonist and the M1 mAChR,
which may involve unusually avid binding of xanomeline to the receptor.
This yields a fraction of added agonist that is retained at the level
of the receptor compartment to persistently bind to and activate the
receptor subsequent to washout. The results of the current study
suggest that elucidation of the mechanism or mechanisms of interaction
of xanomeline with the M1 mAChR is particularly important
in relation to the potential therapeutic use of this agent in the
treatment of Alzheimer's disease.
This article has been cited by other articles:
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  K. C. De Lorme, M. K.O. Grant, M. J. Noetzel, S. B. Polson, and E. E. El-Fakahany Long-Term Changes in the Muscarinic M1 Receptor Induced by Instantaneous Formation of Wash-Resistant Xanomeline-Receptor Complex J. Pharmacol. Exp. Ther., December 1, 2007; 323(3): 868 - 876. [Abstract] [Full Text] [PDF]
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E. Machova, J. Jakubik, E. E. El-Fakahany, and V. Dolezal Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 316 - 323. [Abstract] [Full Text] [PDF]
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 J. Jakubik, E. E. El-Fakahany, and V. Dolezal Differences in Kinetics of Xanomeline Binding and Selectivity of Activation of G Proteins at M1 and M2 Muscarinic Acetylcholine Receptors Mol. Pharmacol., August 1, 2006; 70(2): 656 - 666. [Abstract] [Full Text] [PDF]
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M. K. O. Grant and E. E. El-Fakahany Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M5 Receptor J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 313 - 319. [Abstract] [Full Text] [PDF]
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J. Jakubik, S. Tucek, and E. E. El-Fakahany Role of Receptor Protein and Membrane Lipids in Xanomeline Wash-Resistant Binding to Muscarinic M1 Receptors J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 105 - 110. [Abstract] [Full Text] [PDF]
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J. Jakubik, S. Tucek, and E. E. El-Fakahany Allosteric Modulation by Persistent Binding of Xanomeline of the Interaction of Competitive Ligands with the M1 Muscarinic Acetylcholine Receptor J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1033 - 1041. [Abstract] [Full Text] [PDF]
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A. Christopoulos, M. K. O. Grant, N. Ayoubzadeh, O. N. Kim, P. Sauerberg, L. Jeppesen, and E. E. El-Fakahany Synthesis and Pharmacological Evaluation of Dimeric Muscarinic Acetylcholine Receptor Agonists J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1260 - 1268. [Abstract] [Full Text] [PDF]
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A. Christopoulos, A. M. Parsons, and E. E. El-Fakahany Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1220 - 1228. [Abstract] [Full Text]
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