Pharmacodynamic and pharmacokinetic profile of RBx 343E48F0: A novel, long acting muscarinic receptor antagonist

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• 作者：Suman Gupta ; ¹ ; ^a ; ^{suman.gupta.mm@dsin.co.in} ; Shivani Malhotra¹ ; ^a ; Sandeep Sinha¹ ; ^a ; Shashi K. Singh¹ ; ^a ; Rakesh K. Singh¹ ; ^a ; Siddarangaiah Krishna² ; ^a ; Pooja Chhabra¹ ; ^a ; Tridib Chaira¹ ; ^a ; Janaki Kannayiram¹ ; ^a ; Pradeep Sharma¹ ; ^a ; Shelly Aeron¹ ; ^a ; Jaskiran Kaur³ ; ^a ; Naresh Kumar⁴ ; ^a ; Jitendra Sattigeri¹ ; ^a ; Raj K. Shirumalla¹ ; ^a ; Jyoti Paliwal¹ ; ^a ; Sunanda G. Dastidar¹ ; ^a ; Ian A. Cliffe¹ ; ^a ; Abhijit Ray¹ ; ^a ; Pradip Bhatnagar¹ ; ^a
• 关键词：Muscarinic receptor antagonist ; Chronic Obstructive Pulmonary Disease ; Intratracheal
• 刊名：European Journal of Pharmacology
• 出版年：2011
• 出版时间：11 May 2011
• 年：2011
• 卷：658
• 期：2-3
• 页码：219-228
• 全文大小：549 K

文摘

RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M₃ receptor and a 60-fold selectivity for the M₃ receptor over the M₂ receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK_B of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED₅₀ value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24 h.