Addressing the cognitive symptoms of patients afflicted with Alzheimer's disease represents a critical unmet medical need. Restoring cholinergic signaling, specifically via excitation of the M1 signaling pathway, has been targeted for several decades. Identification of truly selective muscarinic agonists has been hampered due to high sequence homology for these receptors at the orthosteric site, resulting in non-selective agonists like xanomeline. In recent years, targeting allosteric activation has proved more fruitful, resulting in the identification of highly selective, positive allosteric modulators. Herein, we detail and disclose our efforts that led to the discovery of MK-7622, a positive allosteric modulator of the M1 receptor.

Targeting positive allosteric modulators of the M1 muscarinic receptor: Identification of MK-7622

254th National Meeting (2017)

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