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.
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Yasunobu
Y
Yamashita
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Ken-Ichiro
K
Tanaka
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Teita
T
Asano
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Naoki
N
Yamakawa
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Daisuke
D
Kobayashi
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Tomoaki
T
Ishihara
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Kengo
K
Hanaya
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Mitsuru
M
Shoji
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Takeshi
T
Sugai
Technology Research Association for Next Generation Natural Products Chemistry, 2-3-26, Aomi, Koto-ku, Tokyo 135-0064, Japan; Biochemical Information Project, Fujitsu Limited, 1-9-3, Nakase, Mihama-ku, Chiba 261-8588, Japan.
Mitsuhito
M
Wada
Technology Research Association for Next Generation Natural Products Chemistry, 2-3-26, Aomi, Koto-ku, Tokyo 135-0064, Japan; Information and Mathematical Science and Bioinformatics Co., Ltd, Owl Tower, 4-21-1, Higashi-Ikebukuro, Toshima-ku, Tokyo 170-0013, Japan.
Tadaaki
T
Mashimo
Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan.
Yoshifumi
Y
Fukunishi
Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan. Electronic address: mizushima-th@pha.keio.ac.jp.
Tohru
T
Mizushima
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001561:Benzilates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001561:Benzilates; D001993:Bronchodilator Agents; D010880:Piperidines; D043587:Receptor, Muscarinic M3; C005101:mepenzolic acid
COPD; Enantiomers; Mepenzolate bromide; Muscarinic receptor