Interactions of 1-methyl-3-phenylpyrrolidine and 3-methyl-1-phenyl-3-azabicyclo[3.1.0]hexane with monoamine oxidase B.
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 alpha-carbon oxidation of this class of substrates appears to be dependent on the presence of the allylic pi-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)=234microM; V(max)=8.37nmol/(min-mg mitochondrial protein)] and the 3,4-cyclopropyl analogue [K(m)=148microM; V(max)=16.9nmol/(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.
Pretorius
Anél
A
School of Pharmacy, North-West University, Potchefstroom 2520, South Africa.
Ogunrombi
Modupe O
MO
Fourie
Hendrik
H
Terre'blanche
Gisella
G
Castagnoli
Neal
N
Bergh
Jacobus J
JJ
Petzer
Jacobus P
JP
D000818:Animals; D006586:Hexanes / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D020258:Neurotoxicity Syndromes; D010215:Papio; D011759:Pyrrolidines / Q000378:metabolism*
D006586:Hexanes; D011759:Pyrrolidines; D008995:Monoamine Oxidase