Interactions of 1-methyl-3-phenylpyrrolidine and 3-methyl-1-phenyl-3-azabicyclo[3.1.0]hexane with monoamine oxidase B

• Published in: Bioorganic & medicinal chemistry 2010-06, Vol.18 (11), p.4111-4118
• Main Authors: Pretorius, Anél, Ogunrombi, Modupe O., Fourie, Hendrik, Terre’Blanche, Gisella, Castagnoli, Neal, Bergh, Jacobus J., Petzer, Jacobus P.
• Format: Article
• Language: English
• Subjects: 1-Methyl-3-phenyl-3-pyrroline; 1-Methyl-3-phenylpyrrolidine; 3-Methyl-1-phenyl-3-azabicyclo[3.1.0]hexane; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hexanes - metabolism; Kinetics; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous; Mitochondria, Liver - enzymology; Monoamine Oxidase - metabolism; Monoamine oxidase B; Neuropharmacology; Neurotoxicity Syndromes; Neurotransmitters. Neurotransmission. Receptors; Oxidoreductases; Papio; Pharmacology. Drug treatments; Pyrrolidines - metabolism; Saturated substrate
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.03.079

The parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its corresponding five-membered ring analogue 1-methyl-3-phenyl-3-pyrroline are cyclic tertiary allylamines and good substrates of monoamine oxidase B (MAO-B). The MAO-B catalyzed 2-electron α-carbon oxidation of this class of substrates appears to be dependent on the presence of the allylic π-bond since the corresponding saturated piperidinyl analogue of MPTP is reported not to be an MAO-B substrate. The only saturated cyclic tertiary amine known to act as an MAO-B substrate is the 3,4-cyclopropyl analogue of MPTP, 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane. As part of our ongoing studies we have examined the MAO-B substrate properties of the corresponding pyrrolidinyl analogue, 1-methyl-3-phenylpyrrolidine, and the 3,4-cyclopropyl analogue, 3-methyl-1-phenyl-3-azabicyclo[3.1.0]hexane. The results document that both the pyrrolidinyl analogue [ K m = 234 μM; V max = 8.37 nmol/(min-mg mitochondrial protein)] and the 3,4-cyclopropyl analogue [ K m = 148 μM; V max = 16.9 nmol/(min-mg mitochondrial protein)] are substrates of baboon liver mitochondrial MAO-B. We also have compared the neurotoxic potential of these compounds in the C57BL/6 mouse. The results led us to conclude that these compounds are not MPTP-type neurotoxins.