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Effects of Methylphenidate Analogues on Phenethylamine Substrates for the Striatal Dopamine Transporter
Author(s) -
Wayment Hollie K,
Deutsch Howard,
Schweri Margaret,
Schenk James O
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0721266.x
Subject(s) - dopamine transporter , dopamine , chemistry , dopamine plasma membrane transport proteins , phenethylamine , methylphenidate , amphetamine , dopamine uptake inhibitors , stereochemistry , tropane , hydrochloride , ligand (biochemistry) , substrate (aquarium) , transporter , pharmacology , biochemistry , receptor , medicine , biology , attention deficit hyperactivity disorder , ecology , nucleus accumbens , psychiatry , gene
: Methylphenidate (MPD) was found to inhibit competitivelythe striatal dopamine transporter (DAT) and bind at sites on the DAT in commonwith both cocaine (a non‐substrate site ligand) and amphetamine (a substratesite ligand). Some methylphenidate analogues modified on the aromatic ringand/or at the nitrogen were tested to determine whether the profile ofinhibition could be altered. None was found to stimulate the release ofdopamine in the time frame (≤60 s) of the experiments conducted, and eachof the analogues tested was found to non competitively inhibit thetransport of dopamine. It was found that halogenating the aromatic ring withchlorine ( threo ‐3,4‐dichloromethylphenidate hydrochloride ; compound1) increased the affinity of MPD to inhibit the transport of dopamine. Aderivative of MPD with simultaneous, single methyl group substitutions on thephenyl ring and at the nitrogen( threo ‐ N ‐methyl‐4‐methylphenidate hydrochloride ; compound2) bound at a site in common with MPD. A benzyl group positioned at thenitrogen ( threo ‐ N ‐benzylmethylphenidate hydrochloride ;compound 3) imparted properties to the inhibitor in which binding at substrateand non‐substrate sites could be distinguished. This analogue bound at amutually interacting site with that of methylphenidate and had a K int value of 4.29 μ M . 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.