Identification of Mepenzolate Derivatives With Long-Acting Bronchodilatory Activity

• Main Authors: Ken-Ichiro Tanaka (Author), Naoki Yamakawa (Author), Yasunobu Yamashita (Author), Teita Asano (Author), Yuki Kanda (Author), Ayaka Takafuji (Author), Masahiro Kawahara (Author), Mitsuko Takenaga (Author), Yoshifumi Fukunishi (Author), Tohru Mizushima (Author)
• Format: Book
• Published: Frontiers Media S.A., 2018-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2018.00344
• Keywords: chronic obstructive pulmonary disease; anti-inflammatory; long-acting bronchodilatory activity; mepenzolate; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 9 (2018)

The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.