| Summary: | Monoamine oxidase B (MAO-B) is a drug target for the treatment of neurodegenerative
diseases such as Parkinson's disease. For example, the mechanism-based inactivator of MAO-B,
(R)-deprenyl, is frequently used in combination with L-dopa as dopamine replacement
therapy in Parkinson's disease. In contrast with reversible inhibitors, following treatment with
inactivators such as (R)-deprenyl, enzyme activity can only be regained via de novo synthesis of
the MAO-B protein. For this reason, several studies are currently underway to develop safer
inhibitors of MAO-B as an alternative to (R)-deprenyl. These inhibitors are required to be
reversible while retaining selectivity towards MAO-B. We have recently identified (E)-8-(3-
chlorostyryl)caffeine (CSC) as an exceptionally potent reversible inhibitor of MAO-B with an
enzyme-inhibitor dissociation constant (K1 value) of 128 nM. In an attempt to identify the structural features that are responsible for the high inhibition
potency of CSC, we have synthesized six additional analogues of CSC and examined their
MAO-B inhibition potencies in vitro. The analogues chosen for this study are illustrated below.
All of the analogues were found to be reversible inhibitors of baboon liver MAO-B with K, values
in the nano-molar to low micro-molar range. The most potent inhibitor of MAO-B was found to be (E)-8-(3,4-dichlorostyryl)caffeine with a K1 value of 36 nM, approximately 3.5 times more potent than the lead compound CSC. (E)-8-(3-bromostyryl)caffeine was also found to be a potent inhibitor with a K, value of 86 nM, also more potent than the lead compound CSC. The thienyl and furyl substituted compounds proved to be moderate inhibitors with K, values in the low micro-molar range. === Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2007
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