Preventative effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives (N-functional group loading) on MPTP-induced parkinsonism in mice.

Abstract

1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ (1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQ derivatives (loading an N-propyl, N-propenyl, N-propargyl, or N-butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like signs in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me-N-propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQ and 1-Me-N-propyl-TIQ did not. These results suggest that although loading an N-propargyl group on 1-MeTIQ clearly enhanced neuroprotective effects, other N-functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N-functional group may contribute to the observed differences in effect.

• Authors: Hiroko Munakata, Risa Ishikawa, Toshiaki Saitoh, Toshie Kambe, Terumasa Chiba, Kyoji Taguchi, Kenji Abe
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 100 Issue 7 Pg. 594-611 (Jul 01 2022) ISSN: 1205-7541 [Electronic] Canada
• PMID: 35413210 (Publication Type: Journal Article)

Chemical References

• Neuroprotective Agents
• Tetrahydroisoquinolines
• 1-methyl-1,2,3,4-tetrahydroisoquinoline
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Animals
• Humans
• MPTP Poisoning (drug therapy, prevention & control)
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology, therapeutic use)
• Parkinsonian Disorders (chemically induced, drug therapy, prevention & control)
• Tetrahydroisoquinolines