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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	ChemMedChem
Vol/bind	9
Udgave nummer	8
Sider (fra-til)	1677-82
Antal sider	6
ISSN	1860-7179
DOI	https://doi.org/10.1002/cmdc.201402051
Status	Udgivet - aug. 2014
Udgivet eksternt	Ja

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10.1002/cmdc.201402051

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cmdc.201402051

Citationsformater

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.
I: ChemMedChem, Bind 9, Nr. 8, 08.2014, s. 1677-82.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 9, nr. 8, s. 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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T2 - a novel molecular probe

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

Y1 - 2014/8

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.

KW - Acetophenones/chemistry

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

U2 - 10.1002/cmdc.201402051

DO - 10.1002/cmdc.201402051

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JO - ChemMedChem

JF - ChemMedChem

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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

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