The novel quaternary ammonium salt, CHF5407, showed subnanomolar affinities for human muscarinic M1, M2 and M3 receptors, and dissociated very slowly (t1/2 = 166 min from hM3 receptors (t1/2 = 166 min) with a large part of the receptorial complex (54%) remaining undissociated at 32h from radioligand washout. In contrast, [3H]-CHF5407 dissociated quickly from hM2 receptors (t1/2=31 min), whereas [3H]-tiotropium dissociated slowly from both hM3 (t1/2=163 min) and hM2 receptor (t1/2=297 min). In the guinea-pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC50=9.0-9.6) and long-lasting (up to 24h) 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 (i.t.) to anaesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED50 value of 0.15 nmoles/kg. The effect was substained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmoles/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 anaesthetised guinea pigs were not significantly changed by CHF5407, up to 100 nmoles/kg i.v. and up to 1000 nmoles/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, due to a very slow dissociation from M3 receptors. In contrast, CHF5407 is markedly short-acting at M2 receptors, a behaviour not shared by tiotropium.

Bronchodilator Activity of (3R)-3[[[ (3-fluorophenyl) [(3,4,5trifluorophenyl)methyl]amino] oxy]carbonyl]-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 / Villetti, G; Pastore, F; Bergamaschi, M; Bassani, F; Bolzoni, Pt; Battipaglia, L; Amari, G; Rizzi, A; Delcanale, M; Volta, R; Cenacchi, V; Cacciani, Francesca; Zaniboni, Massimiliano; Berti, F; Rossoni, G; Harrison, S; Petrillo, P; Santoro, E; Scudellaro, R; Mannini, F; Geppetti, P; Razzetti, R; Patacchini, R; Civelli, M.. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - 335:(2010), pp. 622-635. [10.1124/jpet.110.170035]

Bronchodilator Activity of (3R)-3[[[ (3-fluorophenyl) [(3,4,5trifluorophenyl)methyl]amino] oxy]carbonyl]-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.

CACCIANI, Francesca;ZANIBONI, Massimiliano;
2010

Abstract

The novel quaternary ammonium salt, CHF5407, showed subnanomolar affinities for human muscarinic M1, M2 and M3 receptors, and dissociated very slowly (t1/2 = 166 min from hM3 receptors (t1/2 = 166 min) with a large part of the receptorial complex (54%) remaining undissociated at 32h from radioligand washout. In contrast, [3H]-CHF5407 dissociated quickly from hM2 receptors (t1/2=31 min), whereas [3H]-tiotropium dissociated slowly from both hM3 (t1/2=163 min) and hM2 receptor (t1/2=297 min). In the guinea-pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC50=9.0-9.6) and long-lasting (up to 24h) 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 (i.t.) to anaesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED50 value of 0.15 nmoles/kg. The effect was substained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmoles/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 anaesthetised guinea pigs were not significantly changed by CHF5407, up to 100 nmoles/kg i.v. and up to 1000 nmoles/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, due to a very slow dissociation from M3 receptors. In contrast, CHF5407 is markedly short-acting at M2 receptors, a behaviour not shared by tiotropium.
Bronchodilator Activity of (3R)-3[[[ (3-fluorophenyl) [(3,4,5trifluorophenyl)methyl]amino] oxy]carbonyl]-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 / Villetti, G; Pastore, F; Bergamaschi, M; Bassani, F; Bolzoni, Pt; Battipaglia, L; Amari, G; Rizzi, A; Delcanale, M; Volta, R; Cenacchi, V; Cacciani, Francesca; Zaniboni, Massimiliano; Berti, F; Rossoni, G; Harrison, S; Petrillo, P; Santoro, E; Scudellaro, R; Mannini, F; Geppetti, P; Razzetti, R; Patacchini, R; Civelli, M.. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - 335:(2010), pp. 622-635. [10.1124/jpet.110.170035]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2319223
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