M₁-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition.

ABSTRACT: Highly selective positive allosteric modulators (PAMs) of the M₁ subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer's disease and schizophrenia. However, excessive activation of M₁ is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M₁ PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M₁ receptor and disrupt PFC function. In contrast, structurall

SUBMITTER: Moran SP 

PROVIDER: S-EPMC6006294 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature