Deuterium isotope effect studies on the MAO-B catalyzed oxidation of 4-benzyl-1-cyclopropyl-1,2,3,6-tetrahydropyridine

Biochemistry
A H AndersonN Castagnoli

Abstract

Previous studies have established that 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is an efficient time- and concentration-dependent inhibitor of the flavin-containing enzyme monoamine oxidase B (MAO-B). This behavior is consistent with a proposed mechanism-based inactivation pathway which proceeds via an initial single electron transfer step to generate an unstable cyclopropylaminyl radical cation intermediate that alkylates an active site functionality via the ring opened primary carbon centered radical. More recently we have found that, in addition to being an inhibitor, the corresponding 1-cyclopropyl-4-benzyl-1,2,3,6-tetrahydropyridine species is an excellent MAO-B substrate, behavior which may not be consistent with the obligatory formation of a cyclopropylaminyl radical cation intermediate. In an attempt to gain further insight into the mechanism associated with the MAO catalyzed oxidation of 1,4-disubstituted tetrahydropyridines, we have undertaken deuterium isotope effect studies on the substrate and inhibitor properties of this 4-benzyl-1-cyclopropyltetrahydropyridine derivative. A normal isotope effect was observed on kcat/KM. Although the good substrate properties of this compound prevented an accurate estimat...Continue Reading

References

Nov 9, 1992·Journal of Medicinal Chemistry·A S Kalgutkar, N Castagnoli
Feb 1, 1991·Biochemical Society Transactions·R B Silverman
Apr 1, 1994·Journal of Medicinal Chemistry·A S KalgutkarN Castagnoli

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Citations

Apr 28, 1999·Bioorganic & Medicinal Chemistry·J Yu, N Castagnoli
Sep 7, 2002·Drug Metabolism Reviews·Neal CastagnoliJackie Shang
Jul 25, 2006·Expert Opinion on Drug Metabolism & Toxicology·Bin Gong, Paul J Boor

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