N‐Methylation of Dopamine‐Derived 6,7‐Dihydroxy‐1,2,3,4‐Tetrahydroisoquinoline, (R)‐Salsolinol, in Rat Brains: In Vivo Microdialysis Study

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Abstract
N‐Methylation of (R)‐1‐methyl‐6,7‐dihydroxy‐1,2,3,4‐tetrahydroisoquinoline [(R)‐salsolinol] derived from dopamine was proved by in vivo microdialysis study in the rat brain. The striatum was perfused with (R)‐salsolinol and N‐methylated compound was identified in the dialysate using HPLC and electrochemical detection with multichanneled electrodes. N‐Methylation of (R)‐salsolinol was confirmed in three other regions of the brain, the substantia nigra, hypothalamus, and hippocampus. In the substantia nigra, the amount of N‐methylated (R)‐salsolinol was significantly larger than in the other three regions. These results indicate that around dopaminergic neurons, particularly in the substantia nigra, (R)‐salsolinol was methylated into N‐methyl‐(R)‐salsolinol, which has a chemical structure similar to that of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine, the selective dopaminergic neurotoxin. N‐Methylation of tetrahydroisoquinolines and β‐carbolines have already been proven to increase their toxicity to dopaminergic neurons and N‐methylation might be an essential step for these alkaloids to increase their toxicity. On the other hand, after perfusion of (R)‐salsolinol, release of dopamine and 5‐hydroxytryptamine was observed and inhibition of monoamine oxidase was indicated. (R)‐Salsolinol and its derivatives may be candidates for being dopaminergic neurotoxins.

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