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

Aaron M. Bender, Hyekyung P. Cho, Kellie D. Nance, Kaelyn S. Lingenfelter, Vincent B. Luscombe, Patrick R. Gentry, Karl Voigtritter, Alice E. Berizzi, Patrick M. Sexton, Christopher J. Langmead, Arthur Christopoulos, 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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1572-1581
Number of pages10
JournalACS Chemical Neuroscience
Volume9
Issue number7
DOIs
Publication statusPublished - 18 Jul 2018

Keywords

  • M
  • muscarinic acetylcholine receptor
  • positive allosteric modulator (PAM)
  • SAR
  • selectivity

Cite this

Bender, Aaron M. ; Cho, Hyekyung P. ; Nance, Kellie D. ; Lingenfelter, Kaelyn S. ; Luscombe, Vincent B. ; Gentry, Patrick R. ; Voigtritter, Karl ; Berizzi, Alice E. ; Sexton, Patrick M. ; Langmead, Christopher J. ; Christopoulos, Arthur ; Locuson, Charles W. ; Bridges, Thomas M. ; Chang, Sichen ; O'Neill, Jordan C. ; Zhan, Xiaoyan ; Niswender, Colleen M. ; Jones, Carrie K. ; Conn, P. Jeffrey ; Lindsley, Craig W. / Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold. In: ACS Chemical Neuroscience. 2018 ; Vol. 9, No. 7. pp. 1572-1581.
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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 = "M, muscarinic acetylcholine receptor, positive allosteric modulator (PAM), SAR, selectivity",
author = "Bender, {Aaron M.} and Cho, {Hyekyung P.} and Nance, {Kellie D.} and Lingenfelter, {Kaelyn S.} and Luscombe, {Vincent B.} and Gentry, {Patrick R.} and Karl Voigtritter and Berizzi, {Alice E.} and Sexton, {Patrick M.} and Langmead, {Christopher J.} and Arthur Christopoulos and Locuson, {Charles W.} and Bridges, {Thomas M.} and Sichen Chang and O'Neill, {Jordan C.} and Xiaoyan Zhan and Niswender, {Colleen M.} and Jones, {Carrie K.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.}",
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Bender, AM, Cho, HP, Nance, KD, Lingenfelter, KS, Luscombe, VB, Gentry, PR, Voigtritter, K, Berizzi, AE, Sexton, PM, Langmead, CJ, Christopoulos, A, Locuson, CW, Bridges, TM, Chang, S, O'Neill, JC, Zhan, X, Niswender, CM, Jones, CK, Conn, PJ & Lindsley, CW 2018, 'Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold' ACS Chemical Neuroscience, vol. 9, no. 7, pp. 1572-1581. https://doi.org/10.1021/acschemneuro.8b00126

Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold. / Bender, Aaron M.; Cho, Hyekyung P.; Nance, Kellie D.; Lingenfelter, Kaelyn S.; Luscombe, Vincent B.; Gentry, Patrick R.; Voigtritter, Karl; Berizzi, Alice E.; Sexton, Patrick M.; Langmead, Christopher J.; Christopoulos, Arthur; Locuson, Charles W.; Bridges, Thomas M.; Chang, Sichen; O'Neill, Jordan C.; Zhan, Xiaoyan; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.

In: ACS Chemical Neuroscience, Vol. 9, No. 7, 18.07.2018, p. 1572-1581.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bender, Aaron M.

AU - Cho, Hyekyung P.

AU - Nance, Kellie D.

AU - Lingenfelter, Kaelyn S.

AU - Luscombe, Vincent B.

AU - Gentry, Patrick R.

AU - Voigtritter, Karl

AU - Berizzi, Alice E.

AU - Sexton, Patrick M.

AU - Langmead, Christopher J.

AU - Christopoulos, Arthur

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AU - Bridges, Thomas M.

AU - Chang, Sichen

AU - O'Neill, Jordan C.

AU - Zhan, Xiaoyan

AU - Niswender, Colleen M.

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

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