Neuronal Nicotinic Receptors: One Hundred Years of Progress

Kellar, Kenneth J.; Xiao, Yingxian

doi:10.1002/9780470101001.hcn004

Cited by 7 publications

(7 citation statements)

References 184 publications

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“…Nicotinic receptors are the prototypical ligand-gated ion channels, and their function is critical to fast synaptic transmission in the central nervous system . While much has been learned about their function, more remains to be learned in order to tease out their roles in disease and normal physiology.…”

Section: Resultsmentioning

confidence: 99%

Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi

et al. 2010

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The skin of the Ecuadorian poison frog Epipedobates anthonyi contains the potent nicotinic agonists, epibatidine (1) and N-methylepibatidine (3). In addition, a condensed tetracyclic epibatidine congener has been identified with activity at nicotinic acetylcholine receptors, but different selectivity than epibatidine. This rigid tetracycle has been named phantasmidine (4). Phantasmidine has a molecular formula of C11H11N2OCl, shares a chloropyridine moiety with 1, and also contains furan, pyrrolidine, and cyclobutane rings. A combination of GC-MS and GC-FTIR analysis with on-column derivatization, 1D NMR spectroscopy with selective irradiation, and spectral simulation, along with 2D NMR were used to elucidate the structure from a total sample of ~20 μg of HPLC-purified 4 and its corresponding acetamide (5). After synthesis, this novel rigid agonist may serve as a selective probe for β4-contaning nicotinic receptors and potentially lead to useful pharmaceuticals.

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Section: Resultsmentioning

confidence: 99%

Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi

et al. 2010

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“…In the CNS, nAChRs mediate fast excitatory post-synaptic responses to the cognate ligand acetylcholine (ACh) and other nicotinic agonists. When nAChRs are activated with ACh, the influx of Na + and Ca 2+ and efflux of K + are effected[1, 2]. …”

Section: Introductionmentioning

confidence: 99%

[ 125 I]Iodo-ASEM, a specific in vivo radioligand for α7-nAChR

Gao

Mease

Olson

et al. 2015

Nuclear Medicine and Biology

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[125I]Iodo-ASEM, a new radioligand with high affinity and selectivity for α7-nAChRs (Ki = 0.5 nM; α7/α4β2 = 3,414), has been synthesized in radiochemical yield of 33 ± 6% from the corresponding di-butyltriazene derivative and at high specific radioactivity (1,600 Ci/mmol; 59.2 MBq/μmol). [125I]Iodo-ASEM readily entered the brains of normal CD-1 mice and specifically and selectively labeled cerebral α7-nAChRs. [125I]iodo-ASEM is a new useful tool for studying α7-nAChR.

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“…[1, 2] Neuronal central nAChR populations are mostly comprised of the homomeric α7-nAChR and heteromeric α4β2-nAChR. [3, 4] These acetylcholine receptor subtypes are involved in great variety of neuronal processes and of interest as targets for therapeutic intervention in a number of conditions and disorders.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of new radioligands [11C]A-833834 and [11C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors

Horti

Ravert

Gao

et al. 2013

Nuclear Medicine and Biology

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Introduction α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer’s disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered. Methods High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with 11C. Baseline and blockade biodistribution studies in the mouse brain of [11C]A-833834 (5-(6-(5-[11C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [11C]A-752274 (2-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [11C]A-752274 was evaluated in a baseline baboon PET study. Results [11C]A-833834 and [11C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12–32%, high specific radioactivity (330–403 GBq/μmol) and radiochemical purity > 95%. Dissection studies with [11C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [11C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [11C]A-752274 exhibited low brain uptake in baboon (%SUV<100). Conclusion Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [11C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [11C]A-752274 exhibited good specific binding in the α7-nAChR – rich mouse brain regions. The low uptake of [11C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.

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Neuronal Nicotinic Receptors: One Hundred Years of Progress

Cited by 7 publications

References 184 publications

Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi

Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi

[ 125 I]Iodo-ASEM, a specific in vivo radioligand for α7-nAChR

Synthesis and evaluation of new radioligands [11C]A-833834 and [11C]A-752274 for positron-emission tomography of α7-nicotinic acetylcholine receptors

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