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A novel and selective monoamine oxidase B substrate.
John M Rimoldi1, Satish G Puppali, Emre Isin
1Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, The University of Mississippi, University, MS 38677, USA. jrimoldi@olemiss.edu
Bioorganic & Medicinal Chemistry
|July 5, 2005
Summary
Cyclic allylamines are oxidized by monoamine oxidase (MAO). A novel saturated cyclic amine analog of MPTP demonstrates MAO substrate properties, suggesting radical stabilization in the catalytic pathway.
Area of Science:
- Biochemistry
- Enzymology
- Organic Chemistry
Background:
- Cyclic allylamines are unique monoamine oxidase (MAO) substrates, undergoing alpha-carbon oxidation to eniminium metabolites.
- Saturated pyrrolidinyl and piperidinyl systems are typically not MAO substrates.
- Investigating substrate properties can elucidate the catalytic mechanisms of flavoenzymes like MAO.
Purpose of the Study:
- To evaluate the role of pi-orbital stabilization in the MAO catalytic pathway.
- To examine the substrate properties of a novel cyclopropyl analog of MPTP.
- To determine if saturated cyclic tertiary amines can be MAO substrates.
Main Methods:
- Synthesis of 3-methyl-6-phenyl-3-aza-bicyclo[4.1.0]heptane, a cyclopropyl analog of MPTP.
- Incubation of the synthesized compound with monoamine oxidase (MAO) enzyme systems.
- Analysis of the reaction products to determine substrate activity.
Main Results:
- The novel saturated cyclic tertiary amine, 3-methyl-6-phenyl-3-aza-bicyclo[4.1.0]heptane, was found to be a substrate for monoamine oxidase.
- This represents the first reported instance of a saturated cyclic tertiary amine exhibiting MAO substrate properties.
- The findings support the hypothesis that alpha-carbon radical stabilization contributes to the MAO catalytic pathway.
Conclusions:
- Saturated cyclic tertiary amines can act as substrates for monoamine oxidase.
- Pi-orbital stabilization of alpha-carbon radical intermediates likely plays a role in the MAO catalytic mechanism.
- This study expands the understanding of MAO substrate specificity and catalytic mechanisms.