Polycyclic aminoguanidines : novel entities for neuroprotection
Wilkes, Dennis Kevin
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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[126.96.36.199(xy2,6).0(xy3,10).0(xy5,9)]undecanea) and 3 (8-imino-N-guanidinopentacyclo[188.8.131.52(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.
- Health Sciences