3-Furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic receptors, produces anxiolytic-like activity in mice

Abstract

Background: Several lines of investigations support the idea that nicotinic acetylcholine receptors modulate neuronal pathways involved in anxiety and depression. Aims: The purpose of this study was to determine whether 3-furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic acetylcholine receptors, influences anxiety-like behaviour in mice, and to determine the modulatory activity of 3-furan-2-yl-N-p-tolyl-acrylamide on mice pretreated with either nicotine or selective α7-agonists (i.e. PNU-282987 or (2.4)-dimethoxybenzylidene anabaseine dihydrochloride). Methods: The elevated plus maze and novelty suppressed feeding tests were selected to evaluate 3-furan-2-yl-N-p-tolyl-acrylamide and other nicotinic ligands on anxiety-like behaviour in mice. Results: The results indicated that: (a) 3-furan-2-yl-N-p-tolyl-acrylamide induces anxiolytic-like activity at 0.5 (elevated plus maze) and 1.0 (novelty suppressed feeding) mg/kg, respectively, after acute treatment, whereas its efficacy is increased after chronic treatments (i.e. active at 0.1 mg/kg; elevated plus maze). This is the first time showing anxiolytic-like activity elicited by 3-furan-2-yl-N-p-tolyl-acrylamide, contrary to the lack of activity for PNU-120596 (0.1 mg/kg); (b) the anxiolytic-like activity of 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide is inhibited by methyllycaconitine, a selective α7-antagonist, suggesting that α7 nicotinic acetylcholine receptors are involved in this process; (c) 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by 0.1 mg/kg nicotine but not by 10.0 mg/kg PNU-282987; and (d) inactive doses of both 3-furan-2-yl-N-p-tolyl-acrylamide (0.1 mg/kg) and (2.4)-dimethoxybenzylidene anabaseine dihydrochloride (1.0 mg/kg) produce anxiolytic-like effects, suggesting drug interactions, probably synergistic. Conclusions: Our findings indicated that anxiolytic-like activity is mediated by α7 nicotinic acetylcholine receptors, supporting the concept that these receptors modulate anxiety processes. The results indicating that the chronic treatment with 3-furan-2-yl-N-p-tolyl-acrylamide is more efficient than the acute treatment in eliciting anxiolytic-like activity, and that 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by nicotine, might be of therapeutic importance during smoking cessation.

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

“…These results confirm the anxiolytic effects of nicotine, which have been previously reported using the same paradigm [4], and emphasise the usefulness of the novel tank diving test as a good model to assess anxiolytic effects. Furthermore, these apparently controversial results, i.e., the anxiolytic effects after nAChR activation or blockade, are in agreement with previous reports showing that both nAChR agonists and antagonists exhibit anxiolytic-like effects in rodents [41][42][43]. Beyond these considerations, our results demonstrate that UFR2709, a novel nAChR antagonist, acts as an anxiolytic drug in this model.…”

(E)-3-Furan-2-yl-N-p-tolyl-acrylamide and its Derivative DM489 Decrease Neuropathic Pain in Mice Predominantly by α7 Nicotinic Acetylcholine Receptor Potentiation

“…This is a consequence of the higher polarity of the secondary amine of PAM-2, which has a H-bond donor, whereas DM489 is a tertiary amine with no H-bond donor (see Figure ). Previous in vivo animal studies showed that intraperitoneal (ip) injections of PAM-2 induced several behavioral effects in mice, − thus suggesting an active brain permeability of PAM-2.…”

Modulation of the mammalian GABAA receptor by type I and type II positive allosteric modulators of the α7 nicotinic acetylcholine receptor

“…Based on their macroscopic mechanism of action, α7‐PAMs are classified as type I (e.g., NS‐1738) and type II modulators (e.g., PNU‐120596 and PAM‐2) that differ in how they modulate the rate of desensitization and reactivate desensitized receptors (Andersen et al, 2016; Arias et al, 2011; Bertrand et al, 2008; Collins et al, 2011; Papke et al, 2018). Preclinical studies have demonstrated that, besides promnesic and procognitive properties likely mediated by potentiation of the α7 nACh receptor, some α7‐PAMs elicit behavioural effects, such as antinociception and anxiolysis, that may be associated with positive modulation of the GABA A receptor (Alzarea & Rahman, 2019; Arias et al, 2020; Potasiewicz et al, 2017, 2015; Quadri et al, 2018; Targowska‐Duda, Budzynska, et al, 2019). However, to the best of our knowledge, there are no published reports on the activity of α7‐PAMs at GABA A receptors.…”