Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold

Abstract

The pharmacology of the M₅ muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M₅ positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M₅ PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M₅ PAM EC₅₀ values <100 nM and rat brain/plasma K_p values of ∼0.40. Interestingly, unlike M₁ and M₄ PAMs with unprecedented mAChR subtype selectivity, this series of M₅ PAMs displayed varying degrees of PAM activity at the other two natively G_q-coupled mAChRs, M₁ and M₃, yet were inactive at M₂ and M₄.

Keywords: M5; SAR; muscarinic acetylcholine receptor; positive allosteric modulator (PAM); selectivity.