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Research ArticleNeuropharmacology

Studies of the Biogenic Amine Transporters. 14. Identification of Low-Efficacy “Partial” Substrates for the Biogenic Amine Transporters

Richard B. Rothman, John S. Partilla, Michael H. Baumann, Catrissa Lightfoot-Siordia and Bruce E. Blough
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 251-262; DOI: https://doi.org/10.1124/jpet.111.188946
Richard B. Rothman
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John S. Partilla
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Michael H. Baumann
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Catrissa Lightfoot-Siordia
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Bruce E. Blough
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Abstract

Several compounds have been identified that display low-efficacy, “partial substrate” activity. Here, we tested the hypothesis that the mechanism of this effect is a slower rate of induced neurotransmitter efflux than that produced by full substrates. Biogenic amine transporter release assays were carried out in rat brain synaptosomes and followed published procedures. [3H]1-methyl-4-phenylpyridinium (MPP+) was used to assess release from dopamine (DA) and norepinephrine nerve terminals, whereas [3H]5-hydroxytryptamine (5-HT) was used to assess release from 5-HT nerve terminals. A detailed time-course evaluation of DA transporter (DAT)-mediated efflux was conducted by measuring the efflux of [3H]MPP+ after the addition of various test compounds. In vivo microdialysis experiments compared the effects of the full substrates [(±)-1-(2-naphthyl)propan-2-amine (PAL-287) and (S)-N-methyl-1-(2-naphthyl)propan-2-amine (PAL-1046)], to that of a partial DAT/5-HT transporter substrate [(S)-N-ethyl-1-(2-naphthyl)propan-2-amine (PAL-1045)] on extracellular DA and 5-HT in the nucleus accumbens of the rat. The in vitro release assays demonstrated that partial substrate activity occurs at all three transporters. In the DAT efflux experiments, d-amphetamine (full substrate) promoted a fast efflux (K1 = 0.24 min−1) and a slow efflux (K2 = 0.008 min−1). For the partial DAT substrates, K1 = ∼0.04 min−1, and K2 approximated zero. The in vivo microdialysis experiments showed that the partial substrate (PAL-1045) was much less effective in elevating extracellular DA and 5-HT than the comparator full substrates. We conclude that low-efficacy partial DAT substrates promote efflux at a slower rate than full substrates, and “partiality” reflects the ultra-slow K2 constant, which functionally limits the ability of these compounds to increase extracellular DA. We speculate that partial biogenic amine transporter substrates bind to the transporter but are less effective in inducing conformational changes required for reverse transport activity.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.188946.

  • ABBREVIATIONS:

    BAT
    biogenic amine transporter
    DA
    dopamine
    DAT
    DA transporter
    5-HT
    5-hydroxytryptamine
    SERT
    5-HT transporter
    NE
    norepinephrine
    NET
    NE transporter
    MPP+
    1-methyl-4-phenylpyridinium
    SA
    specific activity
    NS
    nonspecific binding
    MR
    maximal release
    SR
    specific release
    ANOVA
    analysis of variance
    SAL
    saline
    MDE
    N-ethyl-3,4-methylenedloxyamphetamine
    GBR12935
    1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine
    GBR12909
    1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine
    PAL
    phenethylamine library
    PAL-1063
    4-methyl-thioamphetamine
    PAL-1062
    N,N-dimethyl-4-methyl-thioamphetamine
    PAL-287
    (±)-1-(2-naphthyl)propan-2-amine
    PAL-1046
    (S)-N-methyl-1-(2-naphthyl)propan-2-amine
    PAL-1045
    (S)-N-ethyl-1-(2-naphthyl)propan-2-amine.

  • Received October 10, 2011.
  • Accepted December 19, 2011.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleNeuropharmacology

Partial Substrates for Biogenic Amine Transporters

Richard B. Rothman, John S. Partilla, Michael H. Baumann, Catrissa Lightfoot-Siordia and Bruce E. Blough
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 251-262; DOI: https://doi.org/10.1124/jpet.111.188946

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Research ArticleNeuropharmacology

Partial Substrates for Biogenic Amine Transporters

Richard B. Rothman, John S. Partilla, Michael H. Baumann, Catrissa Lightfoot-Siordia and Bruce E. Blough
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 251-262; DOI: https://doi.org/10.1124/jpet.111.188946
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