AUTHOR=Tanaka Ken-Ichiro , Yamakawa Naoki , Yamashita Yasunobu , Asano Teita , Kanda Yuki , Takafuji Ayaka , Kawahara Masahiro , Takenaga Mitsuko , Fukunishi Yoshifumi , Mizushima Tohru 

TITLE=Identification of Mepenzolate Derivatives With Long-Acting Bronchodilatory Activity

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00344

DOI=10.3389/fphar.2018.00344

ISSN=1663-9812

ABSTRACT=<p>The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that mepenzolate bromide (<bold>MP</bold>), an antagonist for human muscarinic M3 receptor (hM<sub>3</sub>R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain <bold>MP</bold> derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on <bold>MP</bold> and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (<bold>GC</bold>) and aclidinium bromide (<bold>AD</bold>). Of these three synthesized hybrid compounds (<bold>MP-GC, GC-MP, MP-AD</bold>) and <bold>MP, MP-AD</bold> showed the highest affinity for hM<sub>3</sub>R and had the longest lasting bronchodilatory activity, which was equivalent to that of <bold>GC</bold> and <bold>AD</bold>. Both <bold>MP-GC</bold> and <bold>MP-AD</bold> exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with <bold>GC</bold> and <bold>AD, GC-MP</bold> did not show this effect. We also confirmed that administration of <bold>MP-AD</bold> suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of <bold>MP</bold> for both bronchodilatory and anti-inflammatory activities.</p>