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

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.
AuthorsYasunobu 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
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 13 Pg. 3488-97 (Jul 1 2014) ISSN: 1464-3391 [Electronic] England
PMID24844758 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzilates
  • Bronchodilator Agents
  • Piperidines
  • Receptor, Muscarinic M3
  • mepenzolic acid
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, chemistry, pharmacology)
  • Benzilates (administration & dosage, chemistry, pharmacology)
  • Bronchodilator Agents (administration & dosage, chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Heart Rate (drug effects)
  • Male
  • Mice
  • Mice, Inbred ICR
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Piperidines (administration & dosage, chemistry, pharmacology)
  • Pulmonary Disease, Chronic Obstructive (drug therapy)
  • Receptor, Muscarinic M3 (antagonists & inhibitors)
  • Stereoisomerism
  • Structure-Activity Relationship

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