Novel adamantane derivatives as multifunctional neuroprotective agents
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Date
2013
Authors
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Journal ISSN
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Publisher
University of the Western Cape
Abstract
The pathology of neurodegenerative disorders involves multiple steps, and it is probably for
this reason that targeting one particular step in a multi-step process has only yielded limited
results. Nitric oxide (NO) is synthesised from L-Arginine by an enzyme known as nitric
oxide synthase (NOS). Three isoforms of NOS exist, including endothelial NOS (eNOS),
neuronal NOS (nNOS), and inducible NOS (iNOS). In the central nervous system (CNS),
nNOS is involved in the synthesis of NO, which is involved in various neurological
functions. NO is a free radical and this probably explains why an excess amount of it has
been implicated in the development of neurodegenerative disorders. In the CNS, the Nmethyl-
D-aspartate (NMDA) receptor in its active state allows the influx of calcium ions
which activate nNOS thus increasing the amount of NO and other detrimental reactive
nitrogen species within neuronal cells. Calcium entry through voltage-gated calcium channels
(VGCC) may also contribute to this. Although calcium ions are important for physiological
functioning, an excess is responsible for excitotoxicity, which can ultimately lead to
neurodegeneration.
Our aim was to synthesise a series of adamantane-derived compounds that act at multiple
target sites in the neurodegenerative pathway. By conjugating benzyl and phenylethyl
moieties with different functional groups (-H, -NO2, -NH2, -NHC(NH)NH2, -OCH3) to the
amantadine structure, we aimed to synthesise compounds that display calcium channel and
NMDA receptor (NMDAR) channel inhibition, as well as selective inhibition of nNOS.
A series of compounds (-H, -NO2, -NH2, -OCH3) were obtained in yields that varied between
16.5 % and 90.25 %. These novel compounds were tested for calcium influx through VGCC
and NMDAR inhibition using synaptoneurosomes isolated from rat brain homogenate against
the reference compounds MK-801, NGP1-01, amantadine, memantine and nimodipine. A
lack of success with the synthesis of the guanidine compounds prevented the use of the
oxyhemoglobin capture assay for the determination of nNOS inhibitory activity of these
compounds.
The novel synthesised compounds display inhibitory activity towards VGCC and the
NMDAR in the micromolar range. Further tests are recommended on compounds SE-1, SE-4,
SE-11 and SE-12 as they displayed good inhibitory activity against both NMDAR- as well as
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KCl-mediated calcium influx. These novel compounds may be better therapeutic options than
amantadine and memantine as they inhibit both NMDAR and VGCC-mediated calcium
influx, whereas amantadine and memantine only inhibit NMDA-mediated calcium influx.
These novel adamantane derived compounds may possibly serve as novel leads or potential
therapeutic agents for the treatment of neurodegenerative disorders.
Description
>Magister Scientiae - MSc
Keywords
Neurodegenerative disorders, Central nervous system