Targeting selective activation of M₁ for the treatment of Alzheimers disease: Further chemical optimization and pharmacological characterization of the M₁ positive allosteric modulator ML169

The M₁ muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimers disease (AD) and schizophrenia. Moreover, M₁ interacts with BACE1 and regulates its proteosomal degradation, suggesting selective M₁ activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M₁ selective positive allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analogue libraries and probing novel scaffolds. We were able to identify several analogues that possessed submicromolar potency, with our best example displaying an EC₅₀ of 310 nM. The new compounds maintained complete selectivity for the M₁ receptor over the other subtypes (M₂-M₅), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogues were able to potentiate CCh-mediated nonamyloidogenic APPsα release, further strengthening the concept that M₁ PAMs may afford a disease-modifying role in the treatment of AD.