| Summary: | Neurodegenerative diseases such as Parkinson's and Alzheimer's disease as
well as acute disorders for example cerebral ischemia are amongst others
associated with an excess production of nitric oxide (NO) in the central nervous
system. Identification of potent and selective inhibitors of the inducible and
neuronal nitric oxide synthase (NOS) isoforms is therefore of great interest due to
their therapeutic potential in the treatment of these diseases. Recent strategies
in the development of neuroprotective agents for acute and chronic
neurodegenerative disorders also focus on drugs that exhibit antioxidant
properties and drugs that inhibit excitatory amino acid neurotransmission, for
example N-methyl-D-aspartate (NMDA) receptor antagonists.
In this study novel compounds containing the guanidine and pentacyclic cage
moieties were synthesised with the intention of simultaneously addressing NOS
and NMDA receptors as possible target sites. Aminoguanidine (AG) and the
pentacycloundecylamines have been associated with neuroprotection via their
inhibitory and antagonistic effects on inducible NOS and NMDA receptor
channels respectively. Both moieties were therefore included in new structures
with an approach to obtain a dual mechanism for neuroprotection.
The oxyhemoglobin assay was employed to determine the NOS activity of the
above guanylhydrazines and related structures using individual rat brain
homogenate incubations. Although the selectivity of the test compounds were
not accounted for, due to the presence of multiple NOS isoforms, promising NOS
inhibition for the guanylhydrazine compounds was observed.
An increased potency for the novel guanylhydrazine compounds 2 (8-imino-N-guanidino-pentacyclo[5.4.0.0(xy2,6).0(xy3,10).0(xy5,9)]undecanea) and 3 (8-imino-N-guanidinopentacyclo[5.4.0.0(xy2,6).0(xy3,10).0(xy5,9)]undecan-11-one) was observed when compared to AG for in vitro NOS inhibition. The two terminal N-substituted aminoguanidines,
Compounds 2 and 3, presented with IC50 values of 7.6x10-s M and 2.8x10-4Mrespectively. Compared to AG's IC50 value of 2.3x10-3,a 30 and 8 fold increase in
potency was observed. None of the other test compounds showed any significant
activity, suggesting the importance of the carbamidine moiety as a pharmacophore
for effective NOS inhibition.
These results confirm that potent NOS inhibition is achievable by terminal N-substitution of aminoguanidine with the pentacycloundecyl cage structure. In view
of the increase in lipophilicity originating from the pentacycloundecyl cage
structure, it is expected that the new structures will display an increase in blood
brain barrier permeability when compared to AG. The novel compounds represent
a new class of NOS inhibitors and provide the foundation for potential therapeutic
agents. Further analysis regarding the isoform selectivity, the central nervous
system penetration and NMDA receptor activity of these compounds is important.
IX === Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2006.
|
|---|
