Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs), which is highly expressed on the airway smooth muscle, increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. Umeclidinium Bromide is a novel mAChR antagonist with the affinity (Ki) for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. In cells containing the human recombinant M3 mAChR, the CRC (concentration-response curves) obtained with Ach was shifted rightward in the presence of Umeclidinium Bromide (1–1000 nM) in a concentration-dependent manner. Additional cellular studies showed that the effects of Umeclidinium Bromide on the M3 mAChR–mediated activity were slowly reversible. Pretreatment of CHO cells with Umeclidinium Bromide (3.3–330 nM for 30 minutes) produced rightward displacement of the Ach CRC comparable to that obtained previously. The changes in contractile activity were concentration-dependently blocked by preincubation (120 minutes) of the tissues with Umeclidinium Bromide (1–100 nM), thereby displacing the Cch-CRC to the right in a parallel manner. The time to 50% of maximal relaxation(termed ON t1/2) for Umeclidinium Bromide was concentration-dependent and decreased in value as the concentration of antagonist was increased. When administered intranasally as a solution, Umeclidinium Bromide blocked nebulized methacholine (30 mg/ml or ED80 value for maximal bronchoconstriction) in a dose-dependent manner (ED50 = 0.02 μg per mouse measured 5 hours after instillation). Intratracheal instillation of Umeclidinium Bromide (0.25, 2.5, and 25 μg per guinea pig) dose dependently blocked the increase in Penh elicited by aerosolized Ach. At the highest dose of Ach (100 μg i.v.), significant inhibition, i.e., 74.4%, P＜0.05, was obtained 4 hours after instillation of 0.25 μg per guinea pig of Umeclidinium Bromide[3].
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