Allosteric modulation by persistent binding of xanomeline of the interaction of competitive ligands with the M1 muscarinic acetylcholine receptor.

  title={Allosteric modulation by persistent binding of xanomeline of the interaction of competitive ligands with the M1 muscarinic acetylcholine receptor.},
  author={Jan Jakub{\'i}k and Stanislav Tuček and Esam E. El-Fakahany},
  journal={The Journal of pharmacology and experimental therapeutics},
  volume={301 3},
Xanomeline is a potent agonist that is functionally selective for muscarinic M(1) receptors. We have shown previously that a significant fraction of xanomeline binding to membranes of Chinese hamster ovary (CHO) cells expressing the M(1) receptors occurs in a wash-resistant manner and speculated that this persistent binding likely does not take place at the primary binding site on the receptor. In the present work we investigated in depth the pharmacological characteristics of this unique mode… 

Figures and Tables from this paper

Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M5 Receptor

Results clearly indicate that wash-resistant binding of xanomeline to the muscarinic M5 receptor is accompanied by persistent antagonism of receptor function and suggest a relationship between the efficacy of xnomeline and the functional consequences of its wash- resistant binding at different Muscarinic receptor subtypes.

Pharmacological Evaluation of the Long-Term Effects of Xanomeline on the M1 Muscarinic Acetylcholine Receptor

Investigation of the consequences of xanomeline-induced binding of the M1 muscarinic receptor found that blockade of the receptor orthosteric site or the use of a non-functional receptor mutant reversed the long-term effects of xnomeline, but not its persistent binding at an allosteric sites.

Differences in Kinetics of Xanomeline Binding and Selectivity of Activation of G Proteins at M1 and M2 Muscarinic Acetylcholine Receptors

The data support the notion that xanomeline interacts with multiple sites on the muscarinic receptor, resulting in divergent conformations that exhibit differential effects on ligand binding and receptor activation and vary between the M1 and the M2 receptor.

Mechanisms of M3 Muscarinic Receptor Regulation by Wash-Resistant Xanomeline Binding

The data indicate that xanomeline wash-resistant binding at the receptor allosteric site leads to receptor downregulation and that receptor activation is necessary for these effects.

Immediate and Delayed Consequences of Xanomeline Wash-Resistant Binding at the M3 Muscarinic Receptor

Results indicate that xanomeline binds to and activates the M3 muscarinic receptor in a wash-resistant manner, and that this type of binding results in time-dependent receptor regulation.

Long-Term Changes in the Muscarinic M1 Receptor Induced by Instantaneous Formation of Wash-Resistant Xanomeline-Receptor Complex

The results imply that brief exposure to xanomeline followed by washing and prolonged waiting may result in delayed receptor desensitization accompanied by internalization or down-regulation.

Role of Receptor Protein and Membrane Lipids in Xanomeline Wash-Resistant Binding to Muscarinic M1 Receptors

It is suggested that the binding of xanomeline involves interhelical penetration of M1 muscarinic receptor by xanumeline's O-alkyl chain and interaction with membrane lipids surrounding the receptor.

Structure-function studies of M4 muscarinic acetylcholine receptor allosteric modulation

Alanine scanning mutagenesis was utilised in conjunction with radioligand assays to determine the role of specific amino acid residues on affinity or binding cooperativity, and M4 mAChR-mediated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, as a measure of efficacy or functional modulation by LY2033298.



On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor.

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.

The assessment of antagonist potency under conditions of transient response kinetics.

Functionally selective M1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazinylazacycles.

5i was a functionally selective M1 agonist that showed greater functional selectivity than widely studied pyrazinylquinuclidine 5n (L-689,660) and could be attributed to the additional binding interactions between the hexyloxy side chain of 5i and the M1 receptor that are not available to 5n.

Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry

None of the partial agonists showed functional selectivity for M1 receptors, or indeed any muscarinic receptor, in the present study, which shows the value of microphysiometry in being able to compare receptor pharmacology across subtypes irrespective of the signal transduction pathway.

Muscarinic receptor subtypes.

The aim of this review is to discuss the structure, function, and binding properties of the different muscarinic receptor species, attempting where possible to coordinate the diverse experimental data into a uniform picture.

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice.

Xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomelines has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.

The potential for muscarinic receptor subtype-specific pharmacotherapy for Alzheimer's disease.

Stable activation and desensitization of beta 2-adrenergic receptor stimulation of adenylyl cyclase by salmeterol: evidence for quasi-irreversible binding to an exosite.

The unique properties of salmeterol binding to the beta AR, activation of adenylyl cyclase, and desensitization of the hamster beta AR expressed in L cells support the proposal that it binds reversibly to the activating or active site and as well to an extremely high affinity exosite.