| dc.description.abstract | Methylene blue (MB) has diverse medical applications. Among these, MB may act as an
antimalarial agent and has demonstrated potential for the treatment of neurodegenerative
disorders such as Alzheimer’s disease. MB also possesses promising antidepressant and
anxiolytic activity. While MB acts at numerous pharmacological targets, MB is a noteworthy
inhibitor of monoamine oxidase A (MAO-A), exhibiting an in vitro IC50 value of 0.07 μM. MB is
a much less potent MAO-B inhibitor with an IC50 value of 4.37 μM. While MB possesses an
excellent safety profile, in combination with serotonergic agents such as serotonin reuptake
inhibitors, MB can induce serotonin toxicity, which is a direct result of its ability to potently
inhibit MAO-A. It may therefore be advantageous to "design-out" the MAO-A inhibition
properties of MB in order to improve its safety profile. During this study, two new
derivatives of MB were synthesized and their in vitro interactions with recombinant human
MAO-A and MAO-B characterised. The MB analogues, compounds 1 and 2, were
synthesized by reacting phenothiazine with iodine to yield phenothiazin-5-ium tetraiodide
hydrate. This intermediate was subsequently treated with an appropriate amine to yield the
monosubstituted MB analogues. These new compounds were characterised by nuclear
magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). The two MB
analogues were evaluated as potential inhibitors of human MAO-A and MAO-B. The
results showed that compounds 1 and 2 are significantly weaker as MAO-A inhibitors
compared to MB, but display more potent inhibition of the MAO-B isoform compared to MB.
The analogues were also found to be reversible MAO inhibitors, although 2 may exhibit some
tight-binding to MAO-B. Interestingly, the Lineweaver-Burk plots constructed for the inhibition
of the MAOs by 1 and 2 are not typical of competitive inhibition. For the inhibition of MAO-A
by 1, the Lineweaver-Burk plots are indicative of non-competitive inhibition. A modelling study
was carried out to propose potential binding orientations of the MB analogues in MAO-A and
MAO-B. For this study it may be concluded that, compounds (such as 1) that potently inhibit
both MAO-A and MAO-B would be applicable for the treatment of Parkinson’s disease
where depression is a comorbidity. Since MAO-A is inhibited reversibly, the possibility of
tyramine-induced hypertension is reduced. Serotonin toxicity, however, remain a concern of
MB analogues that inhibit MAO-A | en_US |
