Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe

Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Hyekyung P Cho; Emery Smith; Peter Chase; Peter S Hodder; Thomas J Utley; Anuruddha Rajapakse; Frank Byers; Colleen M Niswender; Ryan D Morrison; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley

doi:10.1002/cmdc.201402051

Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe

Patrick R Gentry, Masaya Kokubo, Thomas M Bridges, Hyekyung P Cho, Emery Smith, Peter Chase, Peter S Hodder, Thomas J Utley, Anuruddha Rajapakse, Frank Byers, Colleen M Niswender, Ryan D Morrison, J Scott Daniels, Michael R Wood, P Jeffrey Conn, Craig W Lindsley

15 Citations (Scopus)

Abstract

Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.

Original language	English
Journal	ChemMedChem
Volume	9
Issue number	8
Pages (from-to)	1677-82
Number of pages	6
ISSN	1860-7179
DOIs	https://doi.org/10.1002/cmdc.201402051
Publication status	Published - Aug 2014
Externally published	Yes

Keywords

Acetophenones/chemistry
Animals
Drug Evaluation, Preclinical
Half-Life
Humans
Isoxazoles/chemistry
Molecular Probes/chemistry
Muscarinic Antagonists/chemistry
Protein Binding
Rats
Receptor, Muscarinic M5/antagonists & inhibitors

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Gentry, P. R., Kokubo, M., Bridges, T. M., Cho, H. P., Smith, E., Chase, P., Hodder, P. S., Utley, T. J., Rajapakse, A., Byers, F., Niswender, C. M., Morrison, R. D., Daniels, J. S., Wood, M. R., Conn, P. J., & Lindsley, C. W. (2014). Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe. ChemMedChem, 9(8), 1677-82. https://doi.org/10.1002/cmdc.201402051

Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe. / Gentry, Patrick R; Kokubo, Masaya; Bridges, Thomas M et al.
In: ChemMedChem, Vol. 9, No. 8, 08.2014, p. 1677-82.

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

Gentry, PR, Kokubo, M, Bridges, TM, Cho, HP, Smith, E, Chase, P, Hodder, PS, Utley, TJ, Rajapakse, A, Byers, F, Niswender, CM, Morrison, RD, Daniels, JS, Wood, MR, Conn, PJ & Lindsley, CW 2014, 'Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe', ChemMedChem, vol. 9, no. 8, pp. 1677-82. https://doi.org/10.1002/cmdc.201402051

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abstract = "Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.",

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AU - Gentry, Patrick R

AU - Kokubo, Masaya

AU - Bridges, Thomas M

AU - Cho, Hyekyung P

AU - Smith, Emery

AU - Chase, Peter

AU - Hodder, Peter S

AU - Utley, Thomas J

AU - Rajapakse, Anuruddha

AU - Byers, Frank

AU - Niswender, Colleen M

AU - Morrison, Ryan D

AU - Daniels, J Scott

AU - Wood, Michael R

AU - Conn, P Jeffrey

AU - Lindsley, Craig W

PY - 2014/8

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N2 - Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.

AB - Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450 nM, hM5 Ki=340 nM, M1-M4 IC50>30 μM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.

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KW - Animals

KW - Drug Evaluation, Preclinical

KW - Half-Life

KW - Humans

KW - Isoxazoles/chemistry

KW - Molecular Probes/chemistry

KW - Muscarinic Antagonists/chemistry

KW - Protein Binding

KW - Rats

KW - Receptor, Muscarinic M5/antagonists & inhibitors

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DO - 10.1002/cmdc.201402051

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ER -

Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe

Abstract

Keywords

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