Bronchodilatory and Anti-Inflammatory Effects of ASM-024, a Nicotinic Receptor Ligand, Developed for the Treatment of Asthma

Abstract

Conventional asthma and COPD treatments include the use of bronchodilators, mainly β2-adrenergic agonists, muscarinic receptor antagonists and corticosteroids or leukotriene antagonists as anti-inflammatory agents. These active drugs are administered either separately or given as a fixed-dose combination medication into a single inhaler. ASM-024, a homopiperazinium compound, derived from the structural modification of diphenylmethylpiperazinium (DMPP), has been developed to offer an alternative mechanism of action that could provide symptomatic control through combined anti-inflammatory and bronchodilator properties in a single entity. A dose-dependent inhibition of cellular inflammation in bronchoalveolar lavage fluid was observed in ovalbumin-sensitized mice, subsequently treated for 3 days by nose-only exposure with aerosolized ASM-024 at doses up to 3.8 mg/kg (ED50 = 0.03 mg/kg). The methacholine ED250 values indicated that airway hyperresponsivenness (AHR) to methacholine decreased following ASM-024 administration by inhalation at a dose of 1.5 mg/kg, with a value of 0.145±0.032 mg/kg for ASM 024-treated group as compared to 0.088±0.023 mg/kg for untreated mice. In in vitro isometric studies, ASM-024 elicited dose-dependent relaxation of isolated mouse tracheal, human, and dog bronchial preparations contracted with methacholine and guinea pig tracheas contracted with histamine. ASM-024 showed also a dose and time dependant protective effect on methacholine-induced contraction. Overall, with its combined anti-inflammatory, bronchodilating and bronchoprotective properties, ASM-024 may represent a new class of drugs with a novel pharmacological approach that could prove useful for the chronic maintenance treatment of asthma and, possibly, COPD.

The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF3N,N-diethyl-N′-phenylpiperazine

“…The brain penetration of p-CF 3 diEPP is unknown, thus it is unclear whether there would be in vivo effects associated with a4b2 inhibition. The closely related compound ASM024 is not considered to be a blood-brain barrier penetrant (Assayag et al, 2014). Furthermore, it seems unlikely that antagonism of either a3b4 or a4b2 would have many serious aversive effects given the historical use of the central nervous system-penetrant potent ganglionic antagonist mecamylamine as an antihypertensive therapy (Moyer et al, 1955;McQueen and Smirk, 1957).…”

ASM-024, a Piperazinium Compound, Promotes the In Vitro Relaxation of β2-Adrenoreceptor Desensitized Tracheas

“…Previous in vitr o isometric studies have shown that ASM-024 inhibited the contractile response to methacholine and histamine in a dose-dependent and reversible manner and had a protective effect on methacholine-induced constriction [ 7 ]. In this study, ASM-024 has demonstrated in vitro additive effects with salbutamol in isolated intact dog and human bronchi when added to maximally effective concentrations of salbutamol to even below the applied initial tension.…”

“…Since dog and human bronchi are not easily available, guinea tracheal preparations were used in the desensitization experiments and subsequent loss of responsiveness to β2 agonists. The concentrations used to achieve pharmacological responses in vitro were relatively high, however we have previously shown that doses used in in vivo mouse studies were lower and well within tolerated range [ 7 ]. This apparent discrepancy between in vitro and in vivo doses may be related to the rapid desensitization rate of the nicotinic receptor upon binding of the ligand, essentially resulting in the need for greater and continuous exposure to higher concentrations in order to achieve an in vitro pharmacological effect whereas recovery from the desensitized state may occur more rapidly in vivo [ 14 ].…”

“…ASM-024 is a readily absorbed synthetic homopiperazinium compound which does not cross the blood brain barrier with activity at the nicotinic and muscarinic receptors levels. In preclinical studies, ASM-024 attenuated airway resistance in mice and promoted relaxation of methacholine and histamine-induced contraction of mouse and guinea pig tracheas as well as dog and human bronchi [ 7 ].…”

Effects of Asm‐024, A Modulator of Acetylcholine Receptor Function, On Airway Responsiveness and Allergen‐Induced Responses in Patients with Mild Asthma

“…It acts as a dual anti-inflammatory and bronchodilating agent in preclinical models (10). Although mechanism of action of ASM-024 is still being investigated, observations from whole-cell voltage-clamp experiments have revealed effects on both nicotinic and muscarinic receptors.…”