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 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.
Highlights
Pathological conditions, such as tissue damage, cancer and inflammation, are often accompanied by the acidification of the extracellular environment, which is a primary cause of pain in the sufferer
An effective synthesis scheme was developed both for sevanol and its analogues, which allowed us to perform an investigation of structure–activity relationships
We demonstrated an important role of carboxyl groups for the inhibitory activity of sevanol on the ASIC1a and ASIC3 channels
Summary
Pathological conditions, such as tissue damage, cancer and inflammation, are often accompanied by the acidification of the extracellular environment, which is a primary cause of pain in the sufferer. ASIC3 is widely distributed in the peripheral nervous system and non-neuronal tissues, and is involved in the perception of acid-mediated inflammatory pain (both acute and chronic) [6,7], as well as pain from various mechanical stimuli [8,9] As a result, these channels are regarded as promising targets for the development of analgesic and anti-inflammatory drugs. NMDA receptor channel blockers, such as memantine, IEM-2117 and 9-aminoacridine, inhibit ASIC1a in submillimolar concentrations [15] Most of these compounds are applied in clinics, and they have all demonstrated analgesic, anti-inflammatory or neuroprotective effects in tests in vivo [4,7,11]. Summarizing the stage modifications above, we achieved a significant increase in the overall yield of the total synthesis of sevanol (I) from 3% [27] to 8%, and reduced the number of synthetic procedures to nine steps
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