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. 2006 Aug 29;12(2):100–112. doi: 10.1111/j.1527-3458.2006.00100.x

A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α4β2 Neuronal Nicotinic Acetylcholine Receptor

Lynne E Rueter 1,✉, Diana L Donnelly‐Roberts 1, Peter Curzon 1, Clark A Briggs 1, David J Anderson 1, Robert S Bitner 1
PMCID: PMC6494138  PMID: 16958984

ABSTRACT

A‐85380 [3‐(2(s)‐azetidinylmethoxy) pyridine] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist that has been a useful tool in the investigation of the function of nAChRs in both preclinical and clinical studies. Amongst nAChR subtypes, A‐85380 shows selectivity for the α4β2 vs. the α7 or α1β1δγ nAChRs. In functional in vitro cation flux assays, A‐85380 is a potent and full agonist. A‐85380 has a broad‐spectrum analgesic profile with efficacy in acute, persistent, and neuropathic pain models. As demonstrated using selective nAChR antagonists or α4 antisense, the α4β2 nAChR mediates the analgesic effects of A‐85380. Interestingly, the site of action depends upon the type of pain as antinociception is mediated by descending inhibition into the spinal cord whereas anti‐allodynia in neuropathic pain is mediated at both central and peripheral sites. Radiolabelled forms of A‐85380 have been developed and shown to be safe for use in vivo in humans. In clinical studies using positron and photon emission tomography, marked decreases in α4β2 nAChRs have been seen in patients with Parkinson's and Alzheimer's disease. Although not developed as a therapeutic agent, A‐85380 has proven to be an important component in the development of novel nAChR ligands for the treatment of pain and other disorders.

Keywords: A‐85380, Alzheimer's disease, Neuronal nicotinic acetylcholine receptor, Neuropathic pain, Parkinson's disease, Radioligands, Smoking

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