Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain

  title={Allosteric modulation of $\alpha$4$\beta$2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain},
  author={Deniz Bagdas and Donmez Merve Ergun and Asti B. Jackson and Wisam Toma and Marvin K. Schulte and Mohamad Imad Damaj},
  journal={European Journal of Pain},
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand‐gated ion channels. The α4β2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine‐evoked responses. Agonists and partial agonists of α4β2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non‐selective nAChR agonist with a high affinity for α4β2 nAChRs, is well‐known. There is a growing body of evidence pointing to allosteric modulation of nAChRs… 

Behavioral and Molecular Basis of Cholinergic Modulation of Pain: Focus on Nicotinic Acetylcholine Receptors.

Animal studies suggest that using agonists for α7 nA ChR subtype and antagonists for α9α10 nAChR subtypes are potential novel therapies for chronic pain management, including inflammatory and neuropathic pain.

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

Findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.

Acute Administration of Desformylflustrabromine Relieves Chemically Induced Pain in CD-1 Mice

The results show that desformylflustrabromine is effective in producing an analgesic effect in both tests used for assessing nociception, and suggest that the compound has the potential for pain relief.

Desformylflustrabromine (dFBr), a positive allosteric modulator of α4β2 nicotinic acetylcholine receptors decreases voluntary ethanol consumption and preference in male and female Sprague-Dawley rats

The ability of dF Br to decrease ethanol consumption, along with its previously demonstrated ability to decrease nicotine self-administration in rodents, suggest that dFBr is an attractive therapeutic candidate to target both nicotine and alcohol abuse.

Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats

The results show that the direct acute effect of dFBr is superior to that for CMPI, indicating that selectivity to (α4)3(β2)2 nAChR is not advantageous in alleviating responses to acute thermal nociceptive stimulus.

Allosterism of Nicotinic Acetylcholine Receptors: Therapeutic Potential for Neuroinflammation Underlying Brain Trauma and Degenerative Disorders

The potential of cholinergic allosterism and some allosteric modulators as a promising therapeutic option for the treatment of neuroinflammation is described.



Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors.

Discriminative-stimulus effects of NS9283, a nicotinic α4β2* positive allosteric modulator, in nicotine-discriminating rats

The α4β2* PAM NS9283 alone did not produce nicotine-like discriminative effects, but did demonstrate dose-related increases in nicotine lever choice when combined with a non-effective dose of nicotine or the α4 β2* agonist ABT-594.

Analgesic effects mediated by neuronal nicotinic acetylcholine receptor agonists: correlation with desensitization of α4β2* receptors.

  • Jiahui ZhangYunde Xiao T. Hauser
  • Biology, Chemistry
    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2012

Desformylflustrabromine Modulates α4β2 Neuronal Nicotinic Acetylcholine Receptor High- and Low-Sensitivity Isoforms at Allosteric Clefts Containing the β2 Subunit

Findings from this study will aid in the improved design of dFBr-like PAMs for potential therapeutic use and support the involvement of the principal face of the β2 subunit in dF Br modulation of ACh-induced responses.

Nicotinic acetylcholine receptor agonists: a potential new class of analgesics.

Data from both experimental animals and humans suggest that compounds targeting neuronal nAChRs may represent a new class of analgesic agents, and a discussion of potential mechanisms is provided, including evidence that antinociception is mediated by activation of brainstem nuclei with descending inhibitory inputs to the spinal cord.