JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Christopoulos, A.
Right arrow Articles by El-Fakahany, E. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Christopoulos, A.
Right arrow Articles by El-Fakahany, E. E.

Vol. 289, Issue 3, 1220-1228, June 1999

Pharmacological Analysis of the Novel Mode of Interaction between Xanomeline and the M1 Muscarinic Acetylcholine Receptor1

Arthur Christopoulos, Ann M. Parsons2 and Esam E. El-Fakahany

Departments of Psychiatry (A.C., A.M.P., E.E.E-F.), Neuroscience (E.E.E-F.), and Pharmacology (E.E.E-F.), University of Minnesota Medical School, Minneapolis, Minnesota

Previous findings in our laboratory suggested that the M1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of interaction that involves persistent binding to and activation of the M1 mAChR, subsequent to extensive washout, as well as a possible insurmountable element. In the present study, we examined this interaction in greater detail, using Chinese hamster ovary cells transfected with the genes for the M1 mAChR and neuronal nitric oxide synthase. Pretreatment of cells with xanomeline, followed by extensive washout, resulted in elevated basal levels of neuronal nitric oxide synthase activity that were suppressed by the antagonists atropine or pirenzepine in a concentration-dependent manner. Analysis of the data yielded estimates of Schild slope factors and pKB values for the antagonists that were consistent with a model of simple competition between these latter agents and the persistently bound form of xanomeline. The ability of the antagonists to produce parallel dextral shifts of the concentration-response curves to carbachol and xanomeline was also investigated. The interaction between xanomeline and pirenzepine appeared to be insurmountable, but this may have been due to an equilibrium artifact. In contrast, the interaction between xanomeline and atropine conformed to a model of competition, indicating that the mode of interaction of free xanomeline at the M1 mAChR is pharmacologically identical with that of the persistently bound form. Radioligand binding studies also showed that the presence of various concentrations of xanomeline had no significant effect on the calculated affinity of atropine or pirenzepine in inhibiting the binding of [3H]N-methylscopolamine. Overall, these findings suggest that the persistent attachment of xanomeline to the M1 mAChR does not prevent this agonist from interacting with the classic binding site in a competitive fashion.

0022-3565/99/2893-1220$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 Mol. Pharmacol.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Biol. Chem.Home page
G. J. Lyon, J. S. Wright, A. Christopoulos, R. P. Novick, and T. W. Muir
Reversible and Specific Extracellular Antagonism of Receptor-Histidine Kinase Signaling
J. Biol. Chem., February 15, 2002; 277(8): 6247 - 6253.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.