Currently L-DOPA is the drug most commonly used for the treatment of Parkinson’s disease
(PD). However, the long-term use of L-DOPA is associated with the development of motor
fluctuations and dyskinesias. Treatment mainly addresses the dopaminergic features of the
disease and leaves its progressive course unaffected. An optimal treatment would be a
combination of both motor and non-motor symptom relief with neuroprotective properties. Two
drug targets have attracted the attention for PD treatment, namely monoamine oxidase B (MAOB)
and adenosine A2A receptors. MAO-B inhibitors enhance the elevation of dopamine levels
after L-DOPA treatment, improve motor functions and may also possess neuroprotective
properties. The antagonistic interaction between A2A and dopamine receptors in the
striatopallidal pathway, which modulates motor behaviour, has also become a potential strategy
for PD treatment. Blockade of the A2A receptor exerts both anti-symptomatic and
neuroprotective activities and offer benefit for motor symptoms and motor complications. This
thesis seeks to synthesize novel drug treatments for PD by exploring both MAO-B inhibitors and
adenosine A2A receptor antagonists and to assess the prospects for drug modification to
increase activity.
MAO-B inhibitors -
Based on a recent report that the phthalimide moiety may be a useful scaffold for the design of
potent MAO-B inhibitors, the present study examines a series of 5-sulfanylphthalimide
analogues as potential inhibitors of both human MAO isoforms. The results document that 5-
sulfanylphthalimides are highly potent and selective MAO-B inhibitors with all of the examined
compounds possessing IC50 values in the nanomolar range. The most potent inhibitor, 5-
(benzylsulfanyl)phthalimide, exhibits an IC50 value of 0.0045 μM for the inhibition of MAO-B with
a 427–fold selectivity for MAO-B compared to MAO-A. We conclude that 5-sulfanylphthalimides
represent an interesting class of MAO-B inhibitors and may serve as lead compounds for the
design of antiparkinsonian therapy.
It has recently been reported that nitrile containing compounds frequently act as potent MAO-B
inhibitors. In an attempt to identify additional potent and selective inhibitors of MAO-B and to
contribute to the known structure-activity relationships of MAO inhibition by nitrile containing
compounds, the present study examined the MAO inhibitory properties of series of novel
sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated
compounds are potent and selective MAO-B inhibitors with most homologues possessing IC50
values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding
affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the
compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and
potent MAO-B inhibition (IC50 = 0.025 μM). Based on these observations, this structure may
serve as a lead for the development of therapies for neurodegenerative disorders such as
Parkinson’s disease.
Adenosine A2A receptor antagonism -
Most adenosine A2A receptor antagonists belong to two different chemical classes, the xanthine
derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high
affinity A2A receptor antagonists for PD and to further explore the structure-activity relationships
of A2A antagonism by the xanthine class of compounds, this study examines the A2A
antagonistic properties of series of (E)-8-styrylxanthine, 8-(phenoxymethyl)xanthine and 8-(3-
phenylpropyl)xanthine derivatives. The results document that among these series, the (E)-8-
styrylxanthines are the most potent antagonists with the most potent homologue, (E)-1,3-dietyl-
7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound
was also effective in reversing haloperidol-induced catalepsy in rats. The importance of
substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8-
(phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for
the A2A receptor. It was also concluded that (E)-8-styrylxanthines are potent A2A antagonists
with particularly the 1,3-dietyl-7-methylxanthine substitution pattern being most appropriate for
high affinity binding.
Conclusion -
The results of these studies have established that all of the sulfanylphthalimides,
sulfanylphthalonitriles and sulfanylbenzonitriles examined display significant MAO-B inhibitory
properties in vitro with IC50 values in the low μM to nM range. Good A2A receptor affinity was
demonstrated by the xanthines containing a styryl moiety, while the phenoxymethyl and
phenylpropyl xanthines exhibited poor activity. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/9537 |
| Date | January 2013 |
| Creators | Van der Walt, Mietha Magdalena |
| Publisher | North-West University |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0024 seconds