Interaction of tetrahydrostilbazoles with monoamine oxidase A and B

Abstract

1-Methyl-1,2,3,6-tetrahydrostilbazole (MTHS) and its analogs are oxidized by monoamine oxidase (MAO) A at slow rates comparable to that for the structurally similar neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, but the rates of oxidation by MAO B vary over a wide range depending on the structure of the analog. MAO A oxidation of all of the analogs yielded nonhyperbolic kinetic patterns, with little difference between the cis and trans isomers. In contrast MAO B showed hyperbolic kinetics and distinct stereoselectivity for the cis isomers. The corresponding pyridinium forms of trans-MTHS and its analogs were more potent inhibitors of MAO A (Ki values between 0.3 and 5 microM) than of MAO B, for which the Ki values varied greatly. The data suggest that the stringency of the MAO A active site for the geometry of the substrate molecule is less strict than that of MAO B. With MAO B, any substitution on the phenyl ring can lead to dramatic changes in the substrate properties which may be explained by the different orientation of substrate at the active site of the enzyme. Molecular geometry but not the effects of the substituents was shown to be an important factor in determining the effectiveness of substrate oxidation by MAO B.

A dual-synthon in pyridinium chloride: formation of ladder-like and columnar motifs through hydrogen bonds and cation–π interactions

“…1b. In this paper, we report that a new supramolecular dual-synthon 12 IV was commonly observed in the crystal structures of methylstyrylpyridinium chlorides (1a-1c) 13 and 3-bromo-(2), 14 3-nitro-(3) 15 and 4-trifluorostyrylpyridinium chloride (4) 16 (Fig. 2).…”

Questions in the Chemical Enzymology of MAO

“…It is clear that MAO A and MAO B have different substrate and inhibitor selectivities (for example, [13,[19][20][21]) defined by the distinct hydrophobicity and binding site architectures, but the key region close to the FAD is the same [21]. The chemical mechanism was substantially explored by traditional chemical approaches in the 1990s, but only four mechanisms for oxidation of the amine by MAO have attracted major attention: single electron transfer (SET), the polar nucleophilic mechanism or (as found in some other FAD-dependent oxidases) hydride extraction, and a derivative thereof, two-step hydride transfer [22] (see Figure 1).…”

Substrates but Not Inhibitors Alter the Redox Potentials of Monoamine Oxidases

“…1-Methyl-4-styrylpyridinium is the four-electron oxidation product of 1-methyltetrahydrostilbazole and is a competitive inhibitor of the steady-state turnover of both MAO A (K i 5 6 mM) and B (K i 5 100 mM) (8). It has no effect on the redox potentials for either enzyme (Table 2) The double logarithmic plot for the determination of the redox potential for the oxidized-reduced redox couple in the presence of substrate.…”