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Behavioral Assessments of Spontaneous Locomotion in a Murine MPTP-induced Parkinson's Disease Model
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Vesicular monoamine transporter substrate/inhibitor activity of MPTP/MPP+ derivatives: a structure-activity study

D Shyamali Wimalasena1, Rohan P Perera, Bruce J Heyen

  • 1Department of Chemistry, Wichita State University, Wichita, Kansas 67260-0051, USA.

Journal of Medicinal Chemistry
|January 29, 2008
PubMed

Insights

N-methyl-4-phenylpyridinium (MPP(+)) derivatives were synthesized to study Parkinson

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) metabolite N-methyl-4-phenylpyridinium (MPP(+)) causes Parkinson's disease symptoms.
  • MPP(+) neurotoxicity is linked to mitochondrial complex I inhibition and dopamine metabolism disruption.
  • Understanding MPP(+) neurotoxicity requires studying its derivatives' effects on neuronal processes.

Purpose of the Study:

  • Synthesize and characterize novel MPTP and MPP(+) derivatives.
  • Investigate structure-activity relationships for neurotoxicity, complex I inhibition, and dopamine metabolism perturbation.
  • Identify compounds that modulate vesicular monoamine transporter (VMAT) activity.

Main Methods:

  • Chemical synthesis and characterization of MPTP and MPP(+) derivatives.
  • In vitro studies using bovine chromaffin granule ghosts.
  • Assays to measure VMAT substrate and inhibitor activities.
  • Comparative analysis of neurotoxicity and complex I inhibition.

Main Results:

  • 3'-hydroxy-MPP(+) identified as a potent substrate for VMAT.
  • Novel derivatives combining MPP(+) and VMAT inhibitor features were synthesized.
  • These derivatives demonstrated significant VMAT inhibition.
  • Structure-activity relationships for VMAT substrate and inhibitor activities were defined.

Conclusions:

  • Novel MPTP and MPP(+) derivatives provide tools for Parkinson's disease research.
  • Defined structural requirements for VMAT substrate and inhibitor activities.
  • Insights into mechanisms of MPP(+) neurotoxicity and potential therapeutic targets.

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