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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 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 the 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 the carboxyl groups of the molecule. At the structural level, we predicted the presence of a 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. The 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 the invasive (i.v.) method, thus opening new horizons for medicinal uses of sevanol.

The polypeptide analgesic compounds APCH3 (a TRPV1 receptor inhibitor) and PT1 (a P2X3 receptor inhibitor) were shown not to act on the cardiovascular system or respiratory system when given either as single or multiple doses in mice. The low molecular weight compound sevanol (an ASIC3 receptor inhibitor) had no effect on the cardiovascular system, but prolonged use for 14 days affected measures of the respiratory system, significantly increasing respiratory rate and peak expiratory flow rate. [ABSTRACT FROM AUTHOR]

Previously, a novel lignan sevanol was isolated from Thymus armeniacus, its structure was elucidated; and it was shown that it efficiently inhibits the operation of acid-sensing ion channel ASIC3 and exhibits a pronounced analgesic and anti-inflammatory effect. In this work, the biological activity of a synthetic analogue of sevanol, its stereoisomer, and a precursor compound that represents half of the sevanol molecule was measured in electrophysiological experiments on human ASIC3 channels expressed in Xenopus laevis oocytes. The measured inhibitory activity of a synthetic analogue coincided with the activity of the natural sample; the inhibitory activity of stereoisomer was approximately three times lower, and the precursor was an even less effective inhibitor. Thus, it was shown that the functional groups and stereo configuration of sevanol are essential for its biological activity, which is important to consider while planning the optimal method of its synthesis and development of pharmaceuticals based thereon. [ABSTRACT FROM AUTHOR]

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 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 the 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 the carboxyl groups of the molecule. At the structural level, we predicted the presence of a 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. The 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 the invasive (i.v.) method, thus opening new horizons for medicinal uses of sevanol. [ABSTRACT FROM AUTHOR]