Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities

Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Kengo Hanaya, Mitsuru Shoji, Takeshi Sugai, Mitsuhito Wada, Tadaaki Mashimo, Yoshifumi Fukunishi, Tohru Mizushima

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.

Original languageEnglish
Pages (from-to)3488-3497
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number13
DOIs
Publication statusPublished - 2014 Jul 1

Fingerprint

Muscarinic Antagonists
Enantiomers
Muscarinic Receptors
Anti-Inflammatory Agents
Pulmonary diseases
Chronic Obstructive Pulmonary Disease
mepenzolic acid
Muscarinic M3 Receptors
Stereochemistry
Amines
Condensation
Assays
Carbon
Alcohols

Keywords

  • COPD
  • Enantiomers
  • Mepenzolate bromide
  • Muscarinic receptor

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities. / Yamashita, Yasunobu; Tanaka, Ken Ichiro; Asano, Teita; Yamakawa, Naoki; Kobayashi, Daisuke; Ishihara, Tomoaki; Hanaya, Kengo; Shoji, Mitsuru; Sugai, Takeshi; Wada, Mitsuhito; Mashimo, Tadaaki; Fukunishi, Yoshifumi; Mizushima, Tohru.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 13, 01.07.2014, p. 3488-3497.

Research output: Contribution to journalArticle

Yamashita, Y, Tanaka, KI, Asano, T, Yamakawa, N, Kobayashi, D, Ishihara, T, Hanaya, K, Shoji, M, Sugai, T, Wada, M, Mashimo, T, Fukunishi, Y & Mizushima, T 2014, 'Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities', Bioorganic and Medicinal Chemistry, vol. 22, no. 13, pp. 3488-3497. https://doi.org/10.1016/j.bmc.2014.04.029
Yamashita, Yasunobu ; Tanaka, Ken Ichiro ; Asano, Teita ; Yamakawa, Naoki ; Kobayashi, Daisuke ; Ishihara, Tomoaki ; Hanaya, Kengo ; Shoji, Mitsuru ; Sugai, Takeshi ; Wada, Mitsuhito ; Mashimo, Tadaaki ; Fukunishi, Yoshifumi ; Mizushima, Tohru. / Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 13. pp. 3488-3497.
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AU - Yamakawa, Naoki

AU - Kobayashi, Daisuke

AU - Ishihara, Tomoaki

AU - Hanaya, Kengo

AU - Shoji, Mitsuru

AU - Sugai, Takeshi

AU - Wada, Mitsuhito

AU - Mashimo, Tadaaki

AU - Fukunishi, Yoshifumi

AU - Mizushima, Tohru

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AB - Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.

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