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

Research output: Contribution to journalJournal article

Standard

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

In: ChemMedChem, Vol. 9, No. 8, 08.2014, p. 1677-82.

Research output: Contribution to journalJournal article

Harvard

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

APA

Gentry, P. R., Kokubo, M., Bridges, T. M., Cho, H. P., Smith, E., Chase, P., ... 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

Vancouver

Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P et al. Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe. ChemMedChem. 2014 Aug;9(8):1677-82. https://doi.org/10.1002/cmdc.201402051

Author

Gentry, Patrick R ; Kokubo, Masaya ; Bridges, Thomas M ; Cho, Hyekyung P ; Smith, Emery ; Chase, Peter ; Hodder, Peter S ; Utley, Thomas J ; Rajapakse, Anuruddha ; Byers, Frank ; Niswender, Colleen M ; Morrison, Ryan D ; Daniels, J Scott ; Wood, Michael R ; Conn, P Jeffrey ; Lindsley, Craig W. / Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381) : a novel molecular probe. In: ChemMedChem. 2014 ; Vol. 9, No. 8. pp. 1677-82.

Bibtex

@article{fe9d194eeb6145f29c1db97402b0f0c3,
title = "Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe",
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.",
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",
author = "Gentry, {Patrick R} and Masaya Kokubo and Bridges, {Thomas M} and Cho, {Hyekyung P} and Emery Smith and Peter Chase and Hodder, {Peter S} and Utley, {Thomas J} and Anuruddha Rajapakse and Frank Byers and Niswender, {Colleen M} and Morrison, {Ryan D} and Daniels, {J Scott} and Wood, {Michael R} and Conn, {P Jeffrey} and Lindsley, {Craig W}",
note = "{\circledC} 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",
year = "2014",
month = "8",
doi = "10.1002/cmdc.201402051",
language = "English",
volume = "9",
pages = "1677--82",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "8",

}

RIS

TY - JOUR

T1 - Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381)

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

N1 - © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

M3 - Journal article

C2 - 24692176

VL - 9

SP - 1677

EP - 1682

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 8

ER -

ID: 213599660