[3H]A-585539 [(1S,4S)-2,2-Dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a Novel High-Affinity α7 Neuronal Nicotinic Receptor Agonist: Radioligand Binding Characterization to Rat and Human Brain

Anderson, David J.; Bunnelle, William H.; Surber, Bruce W.; Du, Jia Yan; Surowy, Carol S.; Tribollet, Eliane; Marguerat, Anouk; Bertrand, Daniel; Gopalakrishnan, Murali

doi:10.1124/jpet.107.130062

Cited by 53 publications

(39 citation statements)

References 35 publications

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“…Because the desensitized state of the ␣7 nAChR exhibits a high affinity receptor state and this is the receptor form that is thought to be predominantly expressed during radioligand binding equilibrium conditions, good agreement for ␣7 ligands is expected for electrophysiologically determined IC 50 values and their affinity K i constants. Consistent with this view, we noted the IC 50 value of ϳ10 nM and K i value in the range of 0.4 to 8 nM for ABT-107 in this study, similar to data previously reported for other ␣7 nAChR ligands (Briggs and McKenna, 1998;Anderson et al, 2008).…”

supporting

confidence: 80%

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

Malysz

Anderson²,

Grønlien³

et al. 2010

J Pharmacol Exp Ther

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Enhancement of ␣7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective ␣7 nAChR agonist, 5- 120596)], the addition of ABT-107 elicited MLA-sensitive ␣7 nAChRmediated Ca 2ϩ signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity ␣7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.

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supporting

confidence: 80%

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

Malysz

Anderson²,

Grønlien³

et al. 2010

J Pharmacol Exp Ther

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“…Pellets were thawed, homogenized in BSS-Tris buffer, pH 7.4, and diluted with buffer to approximately 100 (hippocampus) or 150 (frontal cortex) g protein/ aliquot. Binding conditions for the ␣7 nAChR antagonist [ 3 H]MLA and agonist [ 3 H]A-585539 were as described in detail elsewhere (Anderson et al, 2008). Membrane aliquots, ϳ7 nM [ 3 H]MLA (25 Ci/mmol) and 0.1% bovine serum albumin (BSA) in BSS-Tris buffer, pH 7.4, were incubated in quadruplicate in a final volume of 500 l for 60 min at 22°C.…”

Section: Methodsmentioning

confidence: 99%

“…,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539)] radioligand assay were used to determine ␣7 nAChR-binding densities as described previously (Anderson et al, 2008). Briefly, membrane-enriched fractions were prepared fresh from sacrificed male Sprague-Dawley rats, four saline-treated and four treated with ABT-107 (Charles River Laboratories, Inc., Wilmington, MA), 3 to 5 months old.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107: Preclinical Considerations in Alzheimer's Disease

Bitner¹,

Bunnelle²,

Decker³

et al. 2010

J Pharmacol Exp Ther

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We previously reported that ␣7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent ␣7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an ␣7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting ␣7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential therapeutic viability associated with the ␣7 nAChR approach in the treatment of AD.

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“…As described above, the most reliable labeling strategies are the use of a7 nAChR-specific radiolabeled ligands such as a-Btx, MLA, A-585539, CHIBA-1001, AZ11637326, A-582941, A-844606, NS14492, or NS14490 (Han et al, 2003;Tribollet et al, 2004;Anderson et al, 2008;Hashimoto et al, 2008;Toyohara et al, 2010;Ettrup et al, 2011;Maier et al, 2011;Rötering et al, 2014). An alternative approach is to detect a7 nAChR expression levels by measuring the levels of CHRNA7 mRNA, as was performed in monkey brain (Han et al, 2000) and in post mortem human brain (Breese et al, 1997).…”

Section: G Expression and Function Of A7 Nicotinic Acetylcholine Recmentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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[³H]A-585539 [(1S,4S)-2,2-Dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a Novel High-Affinity α7 Neuronal Nicotinic Receptor Agonist: Radioligand Binding Characterization to Rat and Human Brain

Abstract: ABSTRACT

Cited by 53 publications

References 35 publications

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

In Vivo Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107: Preclinical Considerations in Alzheimer's Disease

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

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