Inhibition of dopamine uptake into PC-12 cells by analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The inhibition of uptake of radioactive dopamine into PC-12 cells by analogues of MPTP with systematic variations of structure was studied in order to assess the steric constraints of the transmembrane dopamine transporter. Of 15 analogues tested, 11 were found to inhibit dopamine uptake, all being competitive inhibitors. Major changes to the phenyl ring of MPTP, e.g. replacement of the phenyl by a naphthyl group, had a relatively modest effect on the inhibition of uptake of dopamine. Minor modifications to the N-methyl moiety reduced the ability to inhibit uptake, although the unmethylated analogue still had inhibitory properties. Therefore, in considering environmental agents resembling MPTP as potential causes of idiopathic Parkinson's disease, the size of aromatic groups attached to the alicyclic ring appears not to be critical in terms of the dopamine transporter. Uptake of unmethylated secondary amines is also possible, but these are likely to need to be bioactivated by transamination as well as oxidation to generate neurotoxins.