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

doi: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

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

3 Citations (Scopus)

Abstract

The pharmacology of the M ₅ 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 M ₅ positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M ₅ PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M ₅ PAM EC ₅₀ values <100 nM and rat brain/plasma K _p values of ∼0.40. Interestingly, unlike M ₁ and M ₄ PAMs with unprecedented mAChR subtype selectivity, this series of M ₅ PAMs displayed varying degrees of PAM activity at the other two natively G _q -coupled mAChRs, M ₁ and M ₃ , yet were inactive at M ₂ and M ₄ .

Original language	English
Journal	ACS Chemical Neuroscience
Volume	9
Issue number	7
Pages (from-to)	1572-1581
Number of pages	10
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.8b00126
Publication status	Published - 18 Jul 2018
Externally published	Yes

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Bender, A. M., Cho, H. P., Nance, K. D., Lingenfelter, K. S., Luscombe, V. B., Gentry, P. R., Voigtritter, K., Berizzi, A. E., Sexton, P. M., Langmead, C. J., Christopoulos, A., Locuson, C. W., Bridges, T. M., Chang, S., O'Neill, J. C., Zhan, X., Niswender, C. M., Jones, C. K., Conn, P. J., & Lindsley, C. W. (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, 9(7), 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 et al.
In: ACS Chemical Neuroscience, Vol. 9, No. 7, 18.07.2018, p. 1572-1581.

Research output: Contribution to journal › Journal article › Research › peer-review

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

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title = "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 M 5 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 M 5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M 5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M 5 PAM EC 50 values <100 nM and rat brain/plasma K p values of ∼0.40. Interestingly, unlike M 1 and M 4 PAMs with unprecedented mAChR subtype selectivity, this series of M 5 PAMs displayed varying degrees of PAM activity at the other two natively G q -coupled mAChRs, M 1 and M 3 , yet were inactive at M 2 and M 4 . ",

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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T1 - Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold

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

AU - Locuson, Charles W

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

PY - 2018/7/18

Y1 - 2018/7/18

N2 - The pharmacology of the M 5 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 M 5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M 5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M 5 PAM EC 50 values <100 nM and rat brain/plasma K p values of ∼0.40. Interestingly, unlike M 1 and M 4 PAMs with unprecedented mAChR subtype selectivity, this series of M 5 PAMs displayed varying degrees of PAM activity at the other two natively G q -coupled mAChRs, M 1 and M 3 , yet were inactive at M 2 and M 4 .

AB - The pharmacology of the M 5 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 M 5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M 5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M 5 PAM EC 50 values <100 nM and rat brain/plasma K p values of ∼0.40. Interestingly, unlike M 1 and M 4 PAMs with unprecedented mAChR subtype selectivity, this series of M 5 PAMs displayed varying degrees of PAM activity at the other two natively G q -coupled mAChRs, M 1 and M 3 , yet were inactive at M 2 and M 4 .

U2 - 10.1021/acschemneuro.8b00126

DO - 10.1021/acschemneuro.8b00126

M3 - Journal article

C2 - 29678111

SN - 1948-7193

VL - 9

SP - 1572

EP - 1581

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 7

ER -

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

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