Nitric oxide syntase inhibition by pentacycloundecane conjugates of aminoguanidine and tryptamine
Date
2009Author
Wilkes, Dennis K.
De Vries, Armand
Oliver, Douglas W.
Malan, Sarel F.
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Show full item recordAbstract
This paper describes the synthesis and in-vitro activity of pentacycloundecane-conjugated aminoguanidine
and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate.
Both aminoguanidine and tryptamine-derived NOS inhibitors show selectivity towards the
inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete
inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased
NOS inactivation observed with alkyl substitution of these structures, the present study aimed
to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in
vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC50
values of aminoguanidine (IC50 = 2.306610–3 M) and 8-imino-N-guanidino-pentacyclo-undecane 2
(IC50 = 8.803610– 5 M) revealed a more than 26-fold increase in potency. The ability of tryptamine
to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents.
The compounds, 3-hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11]dodecane
4 and 8-[3-(2-aminoethyl) indole]-pentacyclo[5.4.02,6.03,10.05,9]undecane 7 showed the best
activity of the tryptamine analogues with a more than 3-fold increase in nitric oxide synthase
inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced
the NOS inhibitory potency as observed for the six new NOS inhibitors
URI
http://hdl.handle.net/10394/2825https://onlinelibrary.wiley.com/doi/abs/10.1002/ardp.200800198
https://doi.org/10.1002/ardp.200800198
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- Faculty of Health Sciences [2377]