Metal chelates of L-DOPA for improved replenishment of dopaminergic pools.
An exploratory study consisting of physiochemical and animal experiments was undertaken with the objective of developing one or more metal-L-DOPA chelate systems for an improved transport of L-DOPA into the brain. This approach is based on a theoretical speculation that the pyridoxal-dependent decarboxylation of L-DOPA in the precerebral areas might be obviated by an appropriate metal chelation of the aminocarboxylate end of the L-DOPA molecule. Equilibium studies on the interactions of L-DOPE with Cu2+,Zn2+, Co2+, Mg2+ and Fe2+ ions and their ATP chelates were carried out in order to examine the conditions for the selective binding of the terminal amine group. Metal chelate systems for in vivo transport experiments were selected viz., Cu2+ or Zn2+-L-DOPA (1:2) and Cu2+ or Zn2+-ATP-L-DOPA (1:1:1) which contained the amine-bound metal ion in a completely coordinated form. Results of in vivo studies involving the intraperitoneal administration of 14C-and 3H-LABELED L-DOPA compounds have shown a 100-150% increase in the transport of L-DOPA into the brain by using the Cu2+ and Zn2+ chelates over that effected by using the unchelated L-DOPA. A chromatographic analysis of the brain homogenates showed that only 6% of the overall radioactivity of the brain could be attributed to 3-methoxytyrosine, and the remaining activity was due to DOPA, dopamine and norepinephrine. The transport effectiveness was also compared with that obtained by using the combination drug, RO4-4602 + L-DOPA.
D000818:Animals; D002614:Chelating Agents; D055598:Chemical Phenomena; D002621:Chemistry; D003035:Cobalt / Q000378:metabolism; D003300:Copper / Q000378:metabolism / Q000627:therapeutic use; D007980:Levodopa / Q000378:metabolism* / Q000627:therapeutic use; D008274:Magnesium / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D013997:Time Factors; D015032:Zinc / Q000378:metabolism / Q000627:therapeutic use
D002614:Chelating Agents; D008670:Metals; D003035:Cobalt; D007980:Levodopa; D003300:Copper; D008274:Magnesium; D015032:Zinc