Sevanol and its analogues: chemical synthesis, biological effects and
molecular docking
Abstract
Among acid-sensing ion channels (ASICs), ASIC1a and ASIC3 subunits are
the most widespread and prevalent in physiological and
pathophysiological conditions. They participate in synaptic plasticity,
learning and memory as well as in the perception of inflammatory and
neurological pain, making these channels attractive pharmacological
targets. Sevanol, a natural lignan isolated from Thymus armeniacus,
inhibits the activity of ASIC1a and ASIC3 isoforms and has a significant
analgesic and anti-inflammatory effect. In this work, we described the
efficient chemical synthesis scheme of sevanol and its analogues, which
allows us to analyze the structure-activity relationships of different
parts of this molecule. We found that the inhibitory activity of sevanol
and its analogues on ASIC1a and ASIC3 channels depends on the number and
availability of carboxyl groups of the molecule. At the structural
level, we predicted the presence of sevanol binding site based on the
presence of molecular docking in the central vestibule of the ASIC1a
channel. We predicted that this site could also be occupied in part by
the FRRF-amide peptide, and the competition assay of sevanol with this
peptide confirmed this prediction. Intravenous (i.v.), intranasal (i.n.)
and, especially, oral (p.o.) administration of synthetic sevanol in
animal models produced significant analgesic and anti-inflammatory
effects. Both non-invasive methods of sevanol administration (i.n. and
p.o.) showed greater efficacy than invasive (i.v.) one, thus opening new
horizons for medicinal uses of sevanol.