A Chiral Synthesis of (−)-Spiro[1-azabicyclo[2.2.2]octane-3,5‘- oxazolidin-2‘-one]:  A Conformationally Restricted Analogue of Acetylcholine That Is a Potent and Selective α7 Nicotinic Receptor Agonist

Macor, John E.; Mullen, G. B.; Sampognaro, Anthony J.; Shepardson, Bruce; Mack, R. A.

doi:10.1021/jo049404q

Cited by 28 publications

(12 citation statements)

References 7 publications

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“…The pan-muscarinic agonist muscarine, the preferring M 3 mAChR antagonist darifenacin [13], epibatidine -the preferring agonist of the "ganglionic" nAChRs, such as α3-made nAChRs [14], the α7-preferring antagonist methyllycaconitine [15], the acetylcholinesterase (AChE)-resistant, mixed muscarinic-and-nicotinic agonist CCh, hemicholinium-3 (HC-3), which indirectly affects ACh synthesis by inhibiting high-affinity choline uptake [16,17], and the PKC activator phorbol 12-myristate 13-acetate (PMA) were purchased from Sigma-Aldrich Corp. Inc. (St. Louis, MO). The preferring blockers of α3β2 and α3β4 nAChRs α-conotoxins MII (αCtxMII) and AuIB (αCtxAuIB), respectively, which block their respective target receptors with the IC 50 of 0.5 nM and 0.75 μM and other nAChR subunit combinations with 2-4 orders of magnitude less potent [18][19][20], were synthesized by Advanced ChemTech (Louisville, KY, USA).…”

Section: Cells and Reagentsmentioning

confidence: 99%

Molecular mechanisms of synergy of corneal muscarinic and nicotinic acetylcholine receptors in upregulation of E-cadherin expression

Chernyavsky

Galitovskiy

Grando

2015

International Immunopharmacology

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Section: Cells and Reagentsmentioning

confidence: 99%

Molecular mechanisms of synergy of corneal muscarinic and nicotinic acetylcholine receptors in upregulation of E-cadherin expression

Chernyavsky

Galitovskiy

Grando

2015

International Immunopharmacology

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“…Therefore, a successful radioligand for in vivo imaging of α7-nAChR must display an even higher binding affinity than those currently used for in vivo studies of α4β2-nAChR. In recent years, several classes of selective ligands for α7-nAChR have been discovered [142][143][144][145][146][147]. The quinuclidine series has been reported to display very high affinity for α7-nAChR [146,147] and radiolabeled quinuclidines (Fig.…”

Section: I]α-bungarotoxin ([ 125 I]α-btx) and [ 3 H]methylycaconitinementioning

confidence: 99%

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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Neuronal nicotinic acetylcholine receptors (nAChRs), ubiquitously distributed in the human brain, are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of Alzheimer's and Parkinson's diseases, Tourette's syndrome, epilepsy, schizophrenia, depression, and anxiety, as well as being particularly affected in tobacco dependence/withdrawal. In the past two decades, researchers have developed an extensive series of radioligands for the assessment of nAChRs in vivo through emission tomography, PET and SPECT. Several radioligands, derivatives of A-85380: 2-[(18)F]FA, 6-[(18)F]FA and 5-[(123)I]IA, are now being employed for the evaluation of nAChR in humans with PET and SPECT. Displaying better imaging properties than (11)C-nicotine and a better toxicity profile than epibatidine analogs, they have allowed quantification of thalamic nAChR in the human brain. Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio. Current research efforts on the part of PET/SPECT radiochemists, therefore, have focused on development of new, highly specific and highly selective nAChR radioligands with improved brain kinetics that are able to localize high-affinity nAChRs in vivo. Key examples of new PET/SPECT ligands that are derived from several different structural classes are discussed along with a review of their chemical as well as their in vitro and/or in vivo properties. In particular, new PET nAChR radioligands will be examined that either present faster brain kinetics allowing simple and reliable quantification approaches or higher binding potentials suitable for the evaluation of extrathalamic nAChR.

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“…AR-R17779 is a potent and selective full agonist for α7nAChR. 17 These data suggest that the transiently transfected HEK293T cells cotransfected with α7nAChR+RIC3 form functional channels with a pharmacological profile similar to that of other expression systems and native tissue.…”

Section: Pharmacology Of Hek293t Cells Expressing α7nachr+ric3mentioning

confidence: 84%

A Genome-Wide Arrayed cDNA Screen to Identify Functional Modulators of α7 Nicotinic Acetylcholine Receptors

Rex

Shukla

et al. 2017

SLAS Discovery

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Cellular signaling is in part regulated by the composition and subcellular localization of a series of protein interactions that collectively form a signaling complex. Using the α7 nicotinic acetylcholine receptor (α7nAChR) as a proof-of-concept target, we developed a platform to identify functional modulators (or auxiliary proteins) of α7nAChR signaling. The Broad cDNA library was transiently cotransfected with α7nAChR cDNA in HEK293T cells in a high-throughput fashion. Using this approach in combination with a functional assay, we identified positive modulators of α7nAChR activity. We identified known positive modulators/auxiliary proteins present in the cDNA library that regulate α7nAChR signaling, in addition to identifying novel modulators of α7nAChR signaling. These included NACHO, SPDYE11, TCF4, and ZC3H12A, all of which increased PNU-120596-mediated nicotine-dependent calcium flux. Importantly, these auxiliary proteins did not modulate GluR1(o)-mediated Ca flux. To elucidate a possible mechanism of action, we employed an α7nAChR-HA surface staining assay. NACHO enhanced α7nAChR surface expression; however, the mechanism responsible for the SPDYE11-, TCF4-, and ZC3H12A-dependent modulation of α7nAChR has yet to be defined. This report describes the development and validation of a high-throughput, genome-wide cDNA screening platform coupled to FLIPR functional assays in order to identify functional modulators of α7nAChR signaling.

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A Chiral Synthesis of (−)-Spiro[1-azabicyclo[2.2.2]octane-3,5‘- oxazolidin-2‘-one]: A Conformationally Restricted Analogue of Acetylcholine That Is a Potent and Selective α7 Nicotinic Receptor Agonist

Cited by 28 publications

References 7 publications

Molecular mechanisms of synergy of corneal muscarinic and nicotinic acetylcholine receptors in upregulation of E-cadherin expression

Molecular mechanisms of synergy of corneal muscarinic and nicotinic acetylcholine receptors in upregulation of E-cadherin expression

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

A Genome-Wide Arrayed cDNA Screen to Identify Functional Modulators of α7 Nicotinic Acetylcholine Receptors

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