Allosteric modulation of muscarinic receptors

Jan Jakubik, Esam E. El-Fakahany

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Allosteric ligands modulate binding and function of muscarinic receptors in a different way than orthosteric ligands. Unlike orthosteric ligands their effects are limited by a cooperativity factor. This imparts them unique properties, including cooperativity-based selectivity, functional selectivity and restoring of physiological- like space and time pattern of signaling under pathological conditions. Therefore, allosteric modulators of muscarinic receptor are intensively studied as possible therapeutics of pathological conditions including Alzheimer’s disease and schizophrenia. Research of allosteric modulation has pioneered the way for a whole class A of G-protein coupled receptors and has had an impact beyond its own field. We review principles of allosteric modulations and their implications for proper design of binding as well as functional experiments and for proper data analysis. We demonstrate immense complexity of allosteric modulation of functional responses. Such complexity is reflected in the inability to determine individual microscopic constants in allosterically modulated systems. Therefore, the effects of a given allosteric modulator can be characterized by only two macroscopic parameters, namely a change in the agonist potency and efficacy. We also discuss distinct properties of allosteric interactions that are specific to muscarinic receptors.

Original languageEnglish (US)
Pages (from-to)95-130
Number of pages36
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© Springer Science+Business Media New York 2016.


  • Allosteric modulation
  • Functional response
  • Muscarinic receptors
  • Radioligand binding


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