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 journalArticlepeer-review

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

Keywords

  • COPD
  • Enantiomers
  • Mepenzolate bromide
  • Muscarinic receptor

ASJC Scopus subject areas

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

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