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Research ArticleCellular and Molecular

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

Domenico Tricarico, Jean-François Rolland, Gianluigi Cannone, Antonietta Mele, Valentina Cippone, Antonio Laghezza, Giuseppe Carbonara, Giuseppe Fracchiolla, Paolo Tortorella, Fulvio Loiodice and Diana Conte Camerino
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 266-276; DOI: https://doi.org/10.1124/jpet.111.185835
Domenico Tricarico
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Jean-François Rolland
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Gianluigi Cannone
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Antonietta Mele
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Valentina Cippone
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Antonio Laghezza
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Giuseppe Carbonara
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Giuseppe Fracchiolla
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Paolo Tortorella
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Fulvio Loiodice
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Diana Conte Camerino
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Abstract

The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic β cell ATP-sensitive K+ (KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic β cell KATP channel and the Kir6.2ΔC36 subunit were investigated using a patch-clamp technique. The effects of these compounds on glucose disposal that followed glucose loading by intraperitoneal glucose tolerance test and on fasting glycemia were investigated in normal mice. The 2-n-hexyl analog blocked the KATP (IC50 = 10.1 × 10−9 M) and Kir6.2ΔC36 (IC50 = 9.6 × 10−9 M) channels, which induced depolarization. In contrast, the 2-phenyl analog was a potent opener (drug concentration needed to enhance the current by 50% = 0.04 × 10−9 M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl > 2-benzyl > 2-cyclohexylmethyl. The 2-phenylethyl and 2-isopropyl analogs were not effective as blockers/openers. The 2-n-hexyl (2–10 mg/kg) and 2-phenyl analogs (2–30 mg/kg) reduced and enhanced the glucose areas under the curves, respectively, after glucose loading in mice. These compounds did not affect the fasting glycemia as is observed with glibenclamide. The linear alkyl chain and the aromatic ring at position 2 of the 1,4-benzoxazine nucleus are the determinants, which confer the KATP channel blocking action with glucose-lowering effects and the opening action with increased glucose levels, respectively. The opening/blocking actions of these compounds mimic those that were observed with ATP and ADP. The results support the use of these compounds as novel antidiabetic drugs.

Footnotes

  • This work was supported by the Italian Telethon [Grant GGP10101].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.185835.

  • ABBREVIATIONS:

    KATP
    ATP-sensitive K+
    AUC
    area under the curve
    BPDZ-73
    7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide
    DE50
    drug concentration needed to enhance the current by 50%
    HEK
    human embryonic kidney
    KCO
    KATP channel openers
    Kir6.2
    inwardly rectifying K+ channel
    NBF2
    nucleotide binding fold-2
    TMD2
    second transmembrane domain
    SUR1
    sulfonylureas receptor type-1, BPDZ-62, N-(3,3-dimethylbutan-2-yl)-1,1-dioxo-4H-pyrido[4,3-e][1,2,4]thiadiazin-3-amine
    NNC-55-0118
    6-chloro-1,1-dioxo-N-propan-2-yl-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine
    NN414
    6-chloro-N-(1-methylcyclopropyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine
    NNC-55-0462
    6-chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4thiadiazine 1,1-dioxide.

  • Received July 7, 2011.
  • Accepted October 24, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Research ArticleCellular and Molecular

K+ Channel Modulators and Pancreatic β Cells

Domenico Tricarico, Jean-François Rolland, Gianluigi Cannone, Antonietta Mele, Valentina Cippone, Antonio Laghezza, Giuseppe Carbonara, Giuseppe Fracchiolla, Paolo Tortorella, Fulvio Loiodice and Diana Conte Camerino
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 266-276; DOI: https://doi.org/10.1124/jpet.111.185835

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Research ArticleCellular and Molecular

K+ Channel Modulators and Pancreatic β Cells

Domenico Tricarico, Jean-François Rolland, Gianluigi Cannone, Antonietta Mele, Valentina Cippone, Antonio Laghezza, Giuseppe Carbonara, Giuseppe Fracchiolla, Paolo Tortorella, Fulvio Loiodice and Diana Conte Camerino
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 266-276; DOI: https://doi.org/10.1124/jpet.111.185835
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