Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: Potential as amphetamine antagonists?

Methylphenidate (MPD) was found to inhibit competitively the striatal dopam ine transporter (DAT) and bind at sites on the DAT in common with both coca ine (a non-substrate site ligand) and amphetamine (a substrate site ligand) . Some methylphenidate analogues modified on the aromatic ring and/or at th e nitrogen were tested to determine whether the profile of inhibition could be altered. None was found to stimulate the release of dopamine in the tim e frame (less than or equal to 60 s) of the experiments conducted, and each of the analogues tested was found to noncompetitively inhibit the transpor t of dopamine. It was found that halogenating the aromatic ring with chlori ne (threo-3,4-dichloromethylphenidate hydrochloride; compound 1) increased the affinity of MPD to inhibit the transport of dopamine. A derivative of M PD with simultaneous, single methyl group substitutions on the phenyl ring and at the nitrogen (threo-N-methyl-4-methylphenidate hydrochloride; compou nd 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-substrat e sites could be distinguished. This analogue bound at a mutually interacti ng site with that of methylphenidate and had a K-int value of 4.29 mu M. Fu rthermore, the N-substituted analogues (compounds 2 and 3), although clearl y inhibitors of dopamine transport, were found to attenuate dramatically th e inhibition of dopamine transport by amphetamine, suggesting that the deve lopment of an antagonist for substrate analogue drugs of abuse may be possi ble.