Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues.
The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H(2)O(2) is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (k(inact)/K(i)) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in UV/vis and CD spectral data of the complexes of the studied compounds with both MAO A and MAO B are interpreted in light of crystallographic data of complexes of MAO B with rasagiline and its analogues (Binda, C.; et al. J. Med. Chem. 2004, 47, 1767-1774.
Hubálek
Frantisek
F
Department of Biochemistry, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
Binda
Claudia
C
Li
Min
M
Herzig
Yaacov
Y
Sterling
Jeffrey
J
Youdim
Moussa B H
MB
Mattevi
Andrea
A
Edmondson
Dale E
DE
D000480:Alkynes / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D007189:Indans / Q000737:chemistry*; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000302:isolation & purification; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000480:Alkynes; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; C031967:rasagiline; D008995:Monoamine Oxidase