Diverse Effects on M₁ Signaling and Adverse Effect Liability within a Series of M₁ Ago-PAMs.

ABSTRACT: Both historical clinical and recent preclinical data suggest that the M₁ muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M₁ activation. Efforts then shifted to focus on selective activation of M₁ via either allosteric agonists or positive allosteric modulators (PAMs). While M₁ PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differ

SUBMITTER: Rook JM 

PROVIDER: S-EPMC5460155 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature