Selectivity Optimization of Substituted 1,2,3-Triazoles as α7 Nicotinic Acetylcholine Receptor Agonists

Kuntarat Arunrungvichian, Valery V. Fokin, Opa Vajragupta, Palmer Taylor

Результат исследований: Материалы для журналаСтатья

14 Цитирования (Scopus)

Выдержка

Three series of substituted anti-1,2,3-triazoles (IND, PPRD, and QND), synthesized by cycloaddition from azide and alkyne building blocks, were designed to enhance selectivity and potency profiles of a lead α7 nicotinic acetylcholine receptor (α7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Their functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs, α7-nAChRs, α4β2-nAChRs, and 5HT3A receptors, and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and conformational flexibility of a carbon linker between nitrogen atom and N1 of the triazole. Compounds with a two-carbon atom linker optimized binding with Kds at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the amine center with the highest affinity building blocks in the IND series. Compounds from IND and PPRD series are selective as agonists for the α7-nAChRs over α4β2-nAChRs and 5HT3A receptors. Lead compounds in the three series have EC50s between 28 and 260 nM. Based on the EC50, affinity, and selectivity determined from the binding and cellular responses, two of the leads have been advanced to behavioral studies described in the companion article (DOI: 10.1021/acschemneuro.5b00059).

Язык оригиналаАнглийский
Страницы (с-по)1317-1330
Число страниц14
ЖурналACS Chemical Neuroscience
Том6
Номер выпуска8
DOI
СостояниеОпубликовано - 19 авг 2015
Опубликовано для внешнего пользованияДа

Отпечаток

Cholinergic Agonists
Triazoles
Nicotinic Receptors
Amines
Assays
Carbon
Tropanes
Lead compounds
Atoms
Radioligand Assay
Fluorescence Resonance Energy Transfer
Alkynes
Azides
Cycloaddition
Cycloaddition Reaction
Nitrogen
Complementary DNA
Fluorescence
Cells
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Цитировать

Selectivity Optimization of Substituted 1,2,3-Triazoles as α7 Nicotinic Acetylcholine Receptor Agonists. / Arunrungvichian, Kuntarat; Fokin, Valery V.; Vajragupta, Opa; Taylor, Palmer.

В: ACS Chemical Neuroscience, Том 6, № 8, 19.08.2015, стр. 1317-1330.

Результат исследований: Материалы для журналаСтатья

Arunrungvichian, Kuntarat ; Fokin, Valery V. ; Vajragupta, Opa ; Taylor, Palmer. / Selectivity Optimization of Substituted 1,2,3-Triazoles as α7 Nicotinic Acetylcholine Receptor Agonists. В: ACS Chemical Neuroscience. 2015 ; Том 6, № 8. стр. 1317-1330.
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AU - Arunrungvichian, Kuntarat

AU - Fokin, Valery V.

AU - Vajragupta, Opa

AU - Taylor, Palmer

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N2 - Three series of substituted anti-1,2,3-triazoles (IND, PPRD, and QND), synthesized by cycloaddition from azide and alkyne building blocks, were designed to enhance selectivity and potency profiles of a lead α7 nicotinic acetylcholine receptor (α7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Their functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs, α7-nAChRs, α4β2-nAChRs, and 5HT3A receptors, and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and conformational flexibility of a carbon linker between nitrogen atom and N1 of the triazole. Compounds with a two-carbon atom linker optimized binding with Kds at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the amine center with the highest affinity building blocks in the IND series. Compounds from IND and PPRD series are selective as agonists for the α7-nAChRs over α4β2-nAChRs and 5HT3A receptors. Lead compounds in the three series have EC50s between 28 and 260 nM. Based on the EC50, affinity, and selectivity determined from the binding and cellular responses, two of the leads have been advanced to behavioral studies described in the companion article (DOI: 10.1021/acschemneuro.5b00059).

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KW - cycloaddition reactions

KW - Neurologic disorders

KW - nicotinic acetylcholine receptors

KW - pentameric ligand-gated ion channels

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KW - α7-nAChRs

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