Bronchodilator Activity of (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino] carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407), a Potent, Long-Acting, and Selective Muscarinic M3 Receptor Antagonist

Abstract

The novel quaternary ammonium salt (3R)-3- [[[(3-fluorophenyl) [(3,4,5-trifluorophenyl) H]tiotropium dissociated slowly from both hM3 (t 1 ⁄2 ϭ 163 min) and hM2 receptor (t 1 ⁄2 ϭ 297 min). In the guinea pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC 50 ϭ 9.0 -9.6) and longlasting (up to 24 h) inhibition of M3 receptor-mediated contractile responses to carbachol. In the guinea pig electrically driven left atrium, the M2 receptor-mediated inhibitory response to carbachol was recovered more quickly in CHF5407-pretreated than in tiotropium-pretreated preparations. CHF5407, administered intratracheally to anesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED 50 value of 0.15 nmol/kg. The effect was sustained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmol/kg. In conscious guinea pigs, inhaled CHF5407 inhibited Ach-induced bronchoconstriction for at least 24 h as did tiotropium at similar dosages. Cardiovascular parameters in anesthetized guinea pigs were not significantly changed by CHF5407, up to 100 nmol/kg i.v. and up to 1000 nmol/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, caused by a very slow dissociation from M3

Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs

“…However, although we also documented inhibition of the ozone-induced hypertussive state in guinea pigs following treatment with tiotropium bromide in the present study, we were unable to show any effect of tiotropium bromide on ozone-induced hypertussive responses in the rabbit. This lack of effect was not due to use of an inadequate dose of the muscarinic receptor antagonist, as we used doses clearly capable of inhibiting methacholine-induced bronchoconstriction in this species, confirming previous work in guinea pigs with a related compound, (3 R )-3-[[[(3-fluorophenyl) [(3,4,5-trifluorophenyl)methyl]amino] carbonyl] oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407) ( Villetti et al, 2010 ). Interestingly, ozone also induced bronchial hyper-responsiveness to methacholine, and we plan to further investigate this phenomenon in the future.…”

Muscarinic Receptors and Their Antagonists in COPD: Anti-Inflammatory and Antiremodeling Effects

“…Stimulation of M 3 receptors in the human lung, human central and peripheral airway smooth muscle, and in the human isolated bronchus causes bronchoconstriction and mucus secretion from submucosal glands [18, 27, 29–31]. However, activation of M 3 receptors on vascular endothelial cells also induces the synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes vasodilatation [32].…”

Inhibitory Effect of Ethanolic Extract of Curanga Fel-Terrae (Pugun Tano) Leaves on Acetylcholine Muscarinic-3 Receptors Induced on Isolated Guinea Pig Tracheal

“…Stimulation of ACh-M 3 receptor on the smooth muscle of the airways can cause airway disorders such as bronchoconstriction and increased mucus production from the submucosal glands [18,[30][31][32]. It is known that human muscarinic receptor is predominantly expressed in smooth muscle cells, epithelial cells, and fibroblasts [28].…”