Novel M₁ allosteric ligands: a patent review

Abstract

Introduction: There is substantial evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M₁ muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD) and antipsychotic models of schizophrenia. For example, a number of nonselective M₁ muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M₂ to M₅ subtypes. Thus, there is a need to identify selective activators of the M₁ receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M₁ is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M₁ receptor rather than the highly conserved orthosteric acetylcholine binding site.

Areas covered: This review discusses the M₁ muscarinic receptor and its potential therapeutic value in the treatment of CNS disorders such as AD and schizophrenia. Specifically, novel allosteric ligands that activate or positively modulate the M₁ receptor are examined and peer-reviewed articles associated with these patents publications are also described.

Expert opinion: There is substantial evidence supporting activation of the M₁ receptor might be effective in treating symptoms of AD and schizophrenia, but therapeutic success has been elusive and is hypothesized to be due to the lack of selectivity among orthosteric agonists. During the past decade, allosteric modulation of GPCRs has evolved as a viable strategy toward generating subtype selective molecules. A number of novel, selective ligands in the form of allosteric agonists and positive allosteric modulators of the M₁ receptor have been identified offering the potential for clinical evaluation of M₁-specific receptor activation.

Keywords::

• allosteric
• allosteric agonist
• allosteric modulator
• M₁
• modulators
• PAM

Notes

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