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Muscarinic Acetylcholine Receptor Activators

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Small Molecule Therapeutics for Schizophrenia

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 13))

Abstract

Modulation of muscarinic acetylcholine receptors (mAChRs) is one of the most attractive therapeutic strategies for the treatment of schizophrenia. Pilot clinical studies of the M1/M4 mAChR-preferring agonist xanomeline as well as animal studies using M1–M5 mAChR knockout mice suggest that selective activation of M1 and/or M4 mAChRs is a key concept in the treatment of psychosis and cognitive deficits in patients with schizophrenia. However, over the past two decades, clinical development of mAChR agonists has not been successful mainly due to these agents’ narrow safety margin caused by the lack of true subtype selectivity. However, recent advances in medicinal chemistry might enable researchers to overcome the hurdles that earlier mAChR agonists failed to pass. Here, we describe recent advances in the development of subtype-selective mAChR activators for treatment of schizophrenia.

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Abbreviations

[123I]-IQNB:

[123I]-iodoquinuclidinyl benzilate

ACh:

Acetylcholine

AD:

Alzheimer’s disease

BA:

Bioavailability

BQCA:

Benzylquinolone carboxylic acid

BuTAC:

[5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane

CNS:

Central nervous system

EPS:

Extrapyramidal side effects

Et:

Ethyl

GPCR:

G-protein-coupled receptor

hERG:

Human ether-a-go-go related gene

HTS:

High throughput screening

IA:

Intrinsic activity

mAChR:

Muscarinic acetylcholine receptor

Me:

Methyl

NAM:

Negative allosteric modulator

NDMC:

N-desmethylclozapine

NMDA:

N-methyl-d-aspartate

PAM:

Positive allosteric modulator

PANSS:

Positive and negative syndrome scale

PK:

Pharmacokinetic

PPI:

Prepulse inhibition

TBPB:

1-(1′-(2-tolyl)-1,4′-bipedidin-4-yl)-1H-benzo[d]imidazol-2-(3H)-one

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Authors and Affiliations

  1. Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan

    Takaaki Sumiyoshi

  2. Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka, 564-8680, Japan

    Takaaki Sumiyoshi

  3. Medical Affairs, Drug Development division, Dainippon Sumitomo Pharma Co., Ltd., 13-1 Kyobashi 1-Chome, Chuo-ku, Tokyo, 104-8356, Japan

    Takeshi Enomoto

  4. Drug Development Research Laboratories, Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan

    Takeshi Enomoto

Authors
  1. Takaaki Sumiyoshi
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  2. Takeshi Enomoto
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Correspondence to Takaaki Sumiyoshi .

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Editors and Affiliations

  1. Reigner, France

    Sylvain Celanire

  2. Addex Therapeutics, Geneva, Switzerland

    Sonia Poli

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Sumiyoshi, T., Enomoto, T. (2014). Muscarinic Acetylcholine Receptor Activators. In: Celanire, S., Poli, S. (eds) Small Molecule Therapeutics for Schizophrenia. Topics in Medicinal Chemistry, vol 13. Springer, Cham. https://doi.org/10.1007/7355_2014_47

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