title: Characterization of bencycloquidium bromide, a novel muscarinic M(3) receptor antagonist in guinea pig airways.
abstract: In this study we have investigated the antagonist affinity, efficacy and duration of action of bencycloquidium bromide (BCQB), a selective muscarinic M(3) receptor antagonist, as a possible clinical bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. In competition studies, BCQB showed high affinity toward the M(3) receptor in Chinese hamster ovary (CHO) cells (M(3) pKi=8.21, M(2) pKi=7.21, and M(1) pKi=7.86); pA(2)=8.85, 8.71 and 8.57 in methacholine-induced contraction of trachea, ileum and urinary bladder, 8.19 in methacholine-induced bradycardia of right atrium in vitro, respectively. In function studies, duration of inhibition of carbachol-induced tonic contraction, BCQB and ipratropium had a very similar onset and offset of action, but onset faster and offset slower than that of tiotropium. After treatment with intratracheally instilled or the inhalation route, BCQB protects against methacholine or antigen-induced bronchoconstriction in a dose-dependent manner in the normal and sensitized guinea pigs in vivo. BCQB and ipratropium-induced inhibitory activity was short lasting, as it declined quickly when compared to tiotropium. These results suggest that BCQB bind muscarinic M(3) receptors with high affinity. On this basis we speculate that a putative BCQB-based therapy for COPD might require more than once-a-day administration to be as effective as the currently employed once-daily therapy with tiotropium. Nevertheless, Inhalable M(3)-selective compounds may spare M(2)-cardiac receptors and reduce the risks of cardiovascular events associated with the long-term treatment of these agents.
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Jiang
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.forename: Wan-Ding
authors.initials: WD
authors.lastname: Deng
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.forename: Xin-Wei
authors.initials: XW
authors.lastname: Dong
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Xie
authors.forename: Meng-Jing
authors.initials: MJ
authors.lastname: Bao
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Li
authors.forename: Qiang-Min
authors.initials: QM
authors.lastname: Xie
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D016280:Atrial Function, Right / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D012137:Respiratory System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: D000941:Antigens; D019086:Bridged Bicyclo Compounds, Heterocyclic; D043587:Receptor, Muscarinic M3; C518439:bencycloquidium bromide; D016210:Methacholine Chloride; D002217:Carbachol