title: ASM-024, a piperazinium compound, promotes the in vitro relaxation of β2-adrenoreceptor desensitized tracheas.
abstract: Inhaled β2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. β2-Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the β2-adrenoreceptors (β2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite β2-AR tachyphylaxis. β2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or β2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of β2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than β2-adrenergic receptor agonists. These findings suggest ASM-024 could potentially provide clinical benefit when used adjunctively with inhaled β2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use.
authors: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Québec, Québec, Canada; Asmacure Ltée, Québec, Québec, Canada.
authors: Evelyne
authors: E
authors: Israël-Assayag
authors: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Québec, Québec, Canada.
authors: Marie-Josée
authors: MJ
authors: Beaulieu
authors: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Québec, Québec, Canada; Asmacure Ltée, Québec, Québec, Canada.
authors: Yvon
authors: Y
authors: Cormier
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D009119:Muscle Contraction; D009126:Muscle Relaxation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013618:Tachyphylaxis; D014132:Trachea / Q000187:drug effects / Q000502:physiology*
chemical_list: C000603639:ASM-024; D000067956:Adenylyl Cyclase Inhibitors; D058672:Adrenergic beta-2 Receptor Antagonists; D010879:Piperazines