Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

Sydserff, S G; Sutton, Evelynjeane J.; Song, Dekun; Quirk, Michael C.; Maciag, Carla; Li, Chaoying; Jonak, G J; Gurley, David; Gordon, John; Christian, Edward P.; Doherty, James; Hudzik, Tom; Johnson, Edwin C.; Mrzljak, Ladislav; Piser, Tim; Smagin, Gennady; Wang, Yi; Widzowski, Dan; Smith, Jeffrey S.

doi:10.1016/j.bcp.2009.07.005

Cited by 94 publications

(70 citation statements)

References 26 publications

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“…Successful subcellular localization of a7 nAChRs was obtained using fluorescent a-Btx or immunogold with an anti-a7 nAChR antibody and revealed that in hippocampus, a7 nAChRs are highly expressed presynaptically or perisynaptically, suggesting that these receptors might be involved in a critical role in modulation of the release of other neurotransmitters (Fabian-Fine et al, 2001;Jones and Wonnacott, 2004). The presynaptic role of a7 nAChRs was confirmed by the observation that their stimulation induced the release of other neurotransmitters (Girod et al, 2000;Rousseau et al, 2005;Zhu et al, 2005;Biton et al, 2007;Livingstone et al, 2009;Sydserff et al, 2009;Parikh et al, 2010;Huang et al, 2014a,b;Koranda et al, 2014).…”

Section: G Expression and Function Of A7 Nicotinic Acetylcholine Recmentioning

confidence: 95%

“…, a spirofuropyridine, that has been characterized in preclinical models (Sydserff et al, 2009). AZD0328 was the first spirooxazolidine analog with good selectivity and potency for a7 nAChRs (K i = 3 nM) and showed favorable pharmacokinetic (PK) properties sufficient for advancement into clinical studies.…”

Section: Ligands Active At A7 Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

“…Alzheimer's disease Phase 2 Comentis Briggs et al, 1995;Azuma et al, 1996Azuma et al, , 1999Mahnir et al, 1998;Li et al, 1999;Adams et al, 2000;Crutcher, 2000;Bruchfeld et al, 2010;Loram et al, 2010;Vukelic et al, 2013 Cognitive (Sydserff et al, 2009). In vivo, this compound exhibited activity in a variety of preclinical models including novel object recognition (NOR) in mouse, reversal of short-term memory deficits in fimbria-fornix-lesioned rats, and improvement in working memory in the spatial delayed response task in rhesus monkey (Sydserff et al, 2009;Castner et al, 2011;Werkheiser et al, 2011).…”

Section: Gts-21mentioning

confidence: 99%

“…In vivo, this compound exhibited activity in a variety of preclinical models including novel object recognition (NOR) in mouse, reversal of short-term memory deficits in fimbria-fornix-lesioned rats, and improvement in working memory in the spatial delayed response task in rhesus monkey (Sydserff et al, 2009;Castner et al, 2011;Werkheiser et al, 2011). Quinuiclidine and ring expansion analogs have been extended by modification of functional linkers such as heteroaryls, amides, and carbamates.…”

Section: Gts-21mentioning

confidence: 99%

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Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: G Expression and Function Of A7 Nicotinic Acetylcholine Recmentioning

confidence: 95%

Section: Ligands Active At A7 Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

Section: Gts-21mentioning

confidence: 99%

Section: Gts-21mentioning

confidence: 99%

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Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…Several other novel ␣7 nAChR agonists-(2R)-spiro-[1-azabicyclo[2.2.2]octane-3,2(3H)-furo [2,3-b]pyridine]-tartrate (AZD-0328) (Sydserff et al, 2009), 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide (SEN-12333/WAY-317538) (Roncarati et al, 2009) (Feuerbach et al, 2009), 2[2(4-bromophenyl)-2-oxoethyl]-1-methyl-pyridinium chloride (S24795) (Lopez-Hernandez et al, 2007), and N- [2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (TC-5619) (Hauser et al, 2009)-have been recently described. Although these compounds have provided considerable insight supporting the involvement of ␣7 nAChRs in cognitive and learning functions, the majority of them have inherent limitations.…”

Section: Introductionmentioning

confidence: 99%

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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Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development

Burns

Pei

Wang

2023

Drug Development Research

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The decades‐old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid β1‐42 (Aβ42) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau‐containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra‐high‐affinity interaction between Aβ42 and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug‐related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aβ42's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A–α7nAChR interaction, reduces Aβ42's high‐affinity binding to α7nAChR, and suppresses Aβ42's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease‐modifying treatment for AD.

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Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

Cited by 94 publications

References 26 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

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

Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development

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