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

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 á 4 â 2 vs. the á 7 or á 1 â 1 äã 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 á 4 antisense, the á 4 â 2 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 antiallodynia 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 á 4 â 2 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.

Galantamine-induced improvements in cognitive function are not related to alterations in α4β2 nicotinic receptors in early Alzheimer’s disease as measured in vivo by 2-[18F]Fluoro-A-85380 PET

“…Recently, an α 4 β 2 -subtype-selective radioligand, 3-[2(S)-2-azetidinylmethoxy]pyridine (A-85380) has been developed for in vivo quantification of α 4 β 2 nAChRs using PET Brody et al 2006;Chefer et al 2003;Mitkovski et al 2005; and single photon emission computed tomography imaging (Mitsis et al 2007;O'Brien et al 2007;Staley et al 2005;Ueda et al 2004). The radioligand A-85380 has high affinity (K i =0.048 nM) for α 4 β 2 nAChRs (Rueter et al 2006). Using this ligand, we recently showed no significant differences in regional nAChR distribution volume (DV S ) between drug-naïve early AD patients and healthy age-matched controls (Ellis et al 2008), although Brody et al (2006) recently reported significant (up to 88%) occupancy of α 4 β 2 nAChRs by nicotine following cigarette use, suggesting potential modulation by nicotinic receptor agonists.…”

Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons

“…In pharmacologically relevant antidepressant, anti-nociceptive, and anti-allodynic doses (0.1-1 mg/kg), A-85380 shows considerably lower toxicity than nicotine and epibatidine (Curzon et al, 1998;Rueter et al, 2003Rueter et al, , 2006Buckley et al, 2004). This drug easily penetrates the blood-brain barrier, and in mice has a relatively long half-life (more than 1 h) (Curzon et al, 1998) compared with nicotine that has a halflife of few minutes (Damaj et al, 2007).…”

“…To establish whether a 4 b 2 nAChR stimulation is responsible for the epigenetic modifications in mice caused by nicotine and VAR, we administered A-85380, an agonist Selective a 4 b 2 nicotinic acetylcholine receptor agonists E Maloku et al that binds with subnanomolar affinity to a 4 b 2 but has negligible affinity for a 3 b 4 -or a 7 subtype-containing receptors (Smith et al, 2007;Rueter et al, 2006). In pharmacologically relevant antidepressant, anti-nociceptive, and anti-allodynic doses (0.1-1 mg/kg), A-85380 shows considerably lower toxicity than nicotine and epibatidine (Curzon et al, 1998;Rueter et al, 2003Rueter et al, , 2006Buckley et al, 2004).…”

Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis

“…Competition binding studies with the α 7 -nicAchR selective ligand [ 3 H]-MLA were conducted in rat hippocampal membranes [16, 18]. In contrast to nicotine and lobe-line, lobinaline has similar affinity at α 4 β 2 - and α 7 -nicAchRs ( see Table 2 for comparison ) [80, 81]. Lobinaline produced a DDR value of 1.32, virtually identical to that produced by the CHCl 3 fraction, indicating lobinaline was the main metabolite responsible for the fraction’s nicAchR binding activity.…”

“…The alkaloid inhibited binding of the α 4 β 2 -nicAchR selective ligand [ 3 H]-cytisine (K i = 1.066 μM), and the α 7 -nicAchR selective ligand [ 3 H]-MLA (K i = 67.53 μM), in rat cortical and hippocampal membranes, respectively, and produced a DDR value of 1.32 [1, 16–18]. Compared to other plant metabolites, such as nicotine and lobeline, lobinaline is relatively non-selective with respect to α 4 β 2 - and α 7 -nicAchRs ( see Table 2 for comparison) [80, 81]. The plant metabolite anabasine is also non-selective at α 4 β 2 - and α 7 -nicAchRs (K i = 65 nM and 58 nM at α 4 β 2 - and α 7 -nicAchRs, respectively) [1].…”