Studies on the Monoamine Oxidase-B-Catalyzed Biotransformation of 4-Azaaryl-1-methyl-1,2,3,6-tetrahydropyridine Derivatives

Abstract

The substrate properties of a series of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridinyl (MPTP) analogues in which the C-4 phenyl group has been replaced with various 4-azaaryl moieties have been examined in an effort to evaluate the contribution of electronic, polar, and steric parameters to the MAO-B-catalyzed oxidation of this type of cyclic tertiary allylamine to the corresponding dihydropyridinium metabolite. No significant correlation could be found with the calculated energy of the C-H bond undergoing cleavage. A general trend, however, was observed between the magnitude of the log P value with the magnitude of kcat/Km. The results indicate that the placement of a polar nitrogen atom in the space occupied by the phenyl group of MPTP leads to a dramatic decrease in substrate properties. Enhanced substrate properties, however, were observed when benzoazaarenes replaced the corresponding five-membered azaarenes. These results are consistent with our previously published molecular model of the active site of MAO-B.

Studies on Synthetic Approaches to 1H- and 2H-Indazolyl Derivatives

“…3 As part of our studies designed to explore the structural features that characterize MAO-A and MAO-B substrates, 4 we have synthesized a series of MPTP analogues in which the 4-substituent is a nitrogenlinked triazolyl, pyrrolyl, imidazolyl, benzotriazolyl, indolyl, and indazolyl group (represented by structures A and B). 5 The indazolyl analogues have become of greater interest following reports that 7-nitroindazole (2) displays neuroprotective properties 6 that may be linked to its inhibition of neuronal nitric oxide synthase 7 and/or MAO-B. 8 These reports and our interests in the design of tetrahydropyridinyl prodrugs that may be bioactivated by MAO 9 have prompted us to examine reaction path-ways for the preparation of a variety of 1H-and 2Hindazolyltetrahydropyridinyl derivatives.…”

Measurement of mitochondrial respiration in permeabilized murine neuroblastoma (N-2α) cells, a simple and rapid in situ assay to investigate mitochondrial toxins

“…Nevertheless, optimized conditions for performing Complex III-driven ATP production are included in this paper to provide a complete protocol for this assay. We argue that the mitochondrial inhibition measured for MPTP in earlier studies [18,20] may be explained by the lipophilic nature of MPTP (logP = 2.74; [43]) that would allow it to partition into the inner mitochondrial membrane over a longer period of time (more than 1 h in all the above cases) from where it may start to interfere nonspecifically with the electron transport chain. However, with only 15 min allowed during the in situ mitochondrial respiration assay reported here, there may not have been sufficient time allowed for MPTP to partition as described above.…”

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

“…An ideal MAOB-activated pro-drug should cross the blood–brain barrier and have high MAOB flux and high specificity for MAOB versus MAO-A. The design of the “warhead” attached to the tetrahydropyridine “seeker”, N,N‐bis(2‐chloroethyl) propanamide, was partly based on the size, shape, and LogP of the indolyl and 4-(1-methylpyrrol-2-yl) analogues of MPTP, which have very good MAOB kinetic properties ( Sullivan and Tipton, 1990; Nimkar et al, 1996, 1999 ).…”