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Mode of action and biological activity of sevanol and its analogues on acid-sensing ion channels

P. 183-183.
Osmakov D., Belozerova O., Koshelev S., Andreev Y., Dubinnyi M., Efremov R., Chugunov A., Kublitski V., Kozlov S.

Acid-sensing ion channels (ASICs), members of the family of
amiloride-sensitive degenerin/epithelial
Na + -channels, are expressed in neurons of both the peripheral and central nervous
system. Among six currently known isoforms of mammalian
ASICs, two, namely ASIC1a and ASIC3 are widespread and
have the largest physiological contribution such as synaptic plas-
ticity, learning and memory as well as pain perception and
inflammation development. We have previously shown that seva-
nol, a new lignan isolated from Thymus armeniacus, inhibits
ASIC1a and ASIC3 currents and exerts analgesic and anti-
inflammatory effects when administered intravenously. Here we
present a scheme for the synthesis of sevanol, which was devel-
oped for the first time. In addition, sevanol analogues were syn-
thesized, in which the basic core of the molecule of epiphyllic
acid remained unchanged, while substituents for carboxyl groups
in positions 9,10 were modified. These analogues demonstrate a
clear correlation between the activity of the molecule and the
number of free carboxyl groups in it. Using molecular modeling
and analysis of the activity of sevanol in the presence of ASIC1a
potentiator, an RF-amide peptide, we established a possible bind-
ing site for sevanol on the channel. We also showed that with
intranasal administration, sevanol can have the same effective
analgesic effect as with intravenous administration. Such struc-
tural and functional analysis demonstrates a correlation between
the inhibitory effect value and the number of functional groups
of the molecule, which may be important for the rational design
of biologically active sevanol-based compounds.



























В книге

Под редакцией: M. Purton. Vol. 9: 44th FEBS Congress, From Molecules to Living Systems, Krakow, Poland, July 6‐11, 2019. Oxford: Wiley, 2019.