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

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

  • ACS Chem Neurosci. 2018 Jul 18;9(7):1572-1581. doi: 10.1021/acschemneuro.8b00126.
Aaron M Bender,  Hyekyung P Cho,  Kellie D Nance,  Kaelyn S Lingenfelter,  Vincent B Luscombe,  Patrick R Gentry,  Karl Voigtritter,  Alice E Berizzi 1,  Patrick M Sexton 1,  Christopher J Langmead 1,  Arthur Christopoulos 1,  Charles W Locuson,  Thomas M Bridges,  Sichen Chang,  Jordan C O'Neill,  Xiaoyan Zhan,  Colleen M Niswender,  Carrie K Jones,  P Jeffrey Conn,  Craig W Lindsley
Affiliations

Affiliation

  • 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences , Monash University , Parkville , Victoria 3052 , Australia.
PMID: 29678111 DOI: 10.1021/acschemneuro.8b00126
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 Kp 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 Gq-coupled mAChRs, M1 and M3, yet were inactive at M2 and M4.

Keywords

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

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