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Effects of Methylphenidate Analogues on Phenethylamine Substrates for the Striatal Dopamine Transpor

Effects of Methylphenidate Analogues on Phenethylamine Substrates for the Striatal Dopamine Transpor

  1. NeuroChi
    Abstract: Methylphenidate (MPD) was found to inhibit
    competitively the striatal dopamine transporter (DAT) and
    bind at sites on the DAT in common with both cocaine (a
    non-substrate site ligand) and amphetamine (a substrate
    site ligand). Some methylphenidate analogues modified
    on the aromatic ring and/or at the nitrogen were tested to
    determine whether the profile of inhibition could be altered.
    None was found to stimulate the release of dopamine
    in the time frame (#60 s) of the experiments conducted,
    and each of the analogues tested was found to
    noncompetitively inhibit the transport of dopamine. It was
    found that halogenating the aromatic ring with chlorine
    (threo-3,4-dichloromethylphenidate hydrochloride; compound
    1) increased the affinity of MPD to inhibit the
    transport of dopamine. A derivative of MPD with simultaneous,
    single methyl group substitutions on the phenyl
    ring and at the nitrogen (threo-N-methyl-4-methylphenidate
    hydrochloride; compound 2) bound at a site in common
    with MPD. A benzyl group positioned at the nitrogen
    (threo-N-benzylmethylphenidate hydrochloride; compound
    3) imparted properties to the inhibitor in which
    binding at substrate and non-substrate sites could be
    distinguished. This analogue bound at a mutually interacting
    site with that of methylphenidate and had a Kint
    value of 4.29 mM. Furthermore, the N-substituted analogues
    (compounds 2 and 3), although clearly inhibitors
    of dopamine transport, were found to attenuate dramatically
    the inhibition of dopamine transport by amphetamine,
    suggesting that the development of an antagonist
    for substrate analogue drugs of abuse may be possible.
    Key Words: AmphetamineCocaineDopamineMethylphenidate
    Methylphenidate analogues—Ritalin—Rotating
    disk electrode voltammetry—Striatum—Transporter—
    m-Tyramine.
    J. Neurochem. 72, 1266–1274 (1999).

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