A Novel Multivalent Ligand That Bridges the Allosteric and Orthosteric Binding Sites of the M2 Muscarinic Receptor

  title={A Novel Multivalent Ligand That Bridges the Allosteric and Orthosteric Binding Sites of the M2 Muscarinic Receptor},
  author={Tod Steinfeld and Mathai Mammen and Jacqueline A. M. Smith and Richard D Wilson and Jeffrey R. Jasper},
  journal={Molecular Pharmacology},
  pages={291 - 302}
THRX-160209 is a potent antagonist at the M2 muscarinic acetylcholine (ACh) receptor subtype that was designed using a multivalent strategy, simultaneously targeting the orthosteric site and a nearby site known to bind allosteric ligands. In this report, we describe three characteristics of THRX-160209 binding that are consistent with a multivalent interaction: 1) an apparent affinity of the multivalent ligand for the M2 receptor subtype (apparent pKI = 9.51 ± 0.22) that was several orders of… 

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Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry.

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Two amino acids account entirely for the (approximately 100-fold) M2/M5 selectivity of the alkane-bisammonium and the caracurine V type allosteric ligands at NMS-free M2 receptors.

Multiple allosteric sites on muscarinic receptors.

Use of chimeric muscarinic receptors to investigate epitopes involved in allosteric interactions.

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Application of a Kinetic Model to the Apparently Complex Behavior of Negative and Positive Allosteric Modulators of Muscarinic Acetylcholine Receptors

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Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods.

  • F. Ehlert
  • Biology, Chemistry
    Molecular pharmacology
  • 1988
The theoretical basis for using radioligand binding and pharmacological techniques to estimate the dissociation constants of drugs which interact allosterically with receptors is described and the effect of changes in affinity and intrinsic efficacy of the agonist-receptor complex is predicted.

Two allosteric modulators interact at a common site on cardiac muscarinic receptors.

The results provide the first evidence that two muscarinic allosteric modulators interact competitively at a well defined site.

Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors: interactions of strychnine and acetylcholine at muscarinic receptors.

Novel methods of detecting and quantitating cooperative interactions between an agent and both a tritiated (muscarinic) antagonist and the endogenous agonist (acetylcholine), acting at a common

Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors.

A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for

Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the m2 muscarinic acetylcholine receptor.

The results suggest that the allosteric site for gallamine binding in the m2 receptor residues at or near the putative third outer domain and that both the EDGE motif and Asp-97 play an essential role in the interaction between the two sites.

Allosteric regulation of cloned m1-m5 muscarinic receptor subtypes.