Inhibition of monoamine oxidase by 8-benzyloxycaffeine analogues
Date
2010Author
Strydom, Belinda
Malan, Sarel F.
Bergh, Jacobus J.
Petzer, Jacobus P.
Castagnoli, Neal
Metadata
Show full item recordAbstract
Based on recent reports that several (E)-8-styrylcaffeinyl analogues are potent reversible inhibitors of
monoamine oxidase B (MAO-B), a series of 8-benzyloxycaffeinyl analogues were synthesized and evaluated
as inhibitors of baboon liver MAO-B and recombinant human MAO-A and -B. The 8-benzyloxycaffeinyl
analogues were found to inhibit reversibly both MAO isoforms with enzyme–inhibitor dissociation
constants (Ki values) ranging from 0.14 to 1.30 lM for the inhibition of human MAO-A, and 0.023–
0.59 lM for the inhibition of human MAO-B. The most potent MAO-A inhibitor was 8-(3-methylbenzyloxy)
caffeine while 8-(3-bromobenzyloxy)caffeine was the most potent MAO-B inhibitor. The analogues
inhibited human and baboon MAO-B with similar potencies. A quantitative structure–activity relationship
(QSAR) study indicated that the MAO-B inhibition potencies of the 8-benzyloxycaffeinyl analogues
are dependent on the Hansch lipophilicity (p) and Hammett electronic (r) constants of the substituents
at C-3 of the benzyloxy ring. Electron-withdrawing substituents with a high degree of lipophilicity
enhance inhibition potency. These results are discussed with reference to possible binding orientations
of the inhibitors within the active site cavities of MAO-A and -B.
URI
http://hdl.handle.net/10394/16151https://www.sciencedirect.com/science/article/pii/S0968089609011560
https://doi.org/10.1016/j.bmc.2009.12.064
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