Plant and fungi derived analgesic natural products targeting voltage-gated sodium and calcium channels

Abstract

Voltage-gated sodium and calcium channels (VGSCs and VGCCs) play an important role in the modulation of physiologically relevant processes in excitable cells that range from action potential generation to neurotransmission. Once their expression and/or function is altered in disease, specific pharmacological approaches become necessary to mitigate the negative consequences of such dysregulation. Several classes of small molecules have been developed with demonstrated effectiveness on VGSCs and VGCCs; however, off-target effects have also been described, limiting their use and spurring efforts to find more specific and safer molecules to target these channels. There are a great number of plants and herbal preparations that have been empirically used for the treatment of diseases in which VGSCs and VGCCs are involved. Some of these natural products have progressed to clinical trials, while others are under investigation for their action mechanisms on signaling pathways, including channels. In this review, we synthesize information from ~30 compounds derived from natural sources like plants and fungi and delineate their effects on VGSCs and VGCCs in human disease, particularly pain.

Biosynthetic Pathways of Dimeric Natural Products Containing Bisanthraquinone and Related Xanthones

“…There is a long history for people to use natural plants to treat human diseases, especially in Traditional Chinese Medicine, such as opium for analgesia, and cinchona for malaria [1,2] . Afterwards, natural products as active ingredients extracted from nature resources were found to be effective to those diseases [3–5] . Therefore, numerous natural products have been developed as the pharmaceuticals or the lead compounds in drug discovery research, such as glycopeptides vancomycin and β‐lactams for anti‐inflammation, lovastatin for cholesterol lowering, morphine and codeine for analgesia, as well as taxol for anti‐tumor [6–8] .…”

“…[1,2] Afterwards, natural products as active ingredients extracted from nature resources were found to be effective to those diseases. [3][4][5] Therefore, numerous natural products have been developed as the pharmaceuticals or the lead compounds in drug discovery research, such as glycopeptides vancomycin and β-lactams for anti-inflammation, lovastatin for cholesterol lowering, morphine and codeine for analgesia, as well as taxol for anti-tumor. [6][7][8] However, their supply has often been limited because of the low yield for extraction from natural resources, and tedious total synthesis steps for extremely complex structures of natural products and being rich in chiral centers.…”

C–H Functionalization-Enabled 11-Step Semisynthesis of (−)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment

“…Chronic pain affects 20–30% of the global population . Traditional remedies from plants, such as opium poppy-derived morphine, willow bark-based aspirin, and cannabis-origin tetrahydrocannabinol (THC), have historically treated various types of pain . Despite opioids being central to pain management, they have limitations and serious side effects, prompting the search for alternative antinociceptive therapies.…”

“…(−)-Veragranines A (1, Figure 1A) and B (2) are two cholestane steroidal alkaloids isolated by Luo and co-workers from Veratrum grandiflorum, an important ingredient of traditional herbal medicine often used for pain and inflammation treatment. 5 Biologically, veragranines A and B were reported to block the N-type calcium channels (Ca v 2.2) with IC 50 values of 45.76 ± 1.14 and 7.82 ± 1.10 μM, respectively, and have analgesic effect at 1.0 and 0.5 mg/kg in male mice models with acetic acid-induced writhing pain.…”

“… 1 Traditional remedies from plants, such as opium poppy-derived morphine, willow bark-based aspirin, and cannabis-origin tetrahydrocannabinol (THC), have historically treated various types of pain. 2 Despite opioids being central to pain management, they have limitations and serious side effects, 3 prompting the search for alternative antinociceptive therapies. Extensive pain research has elucidated crucial neuronal mechanisms that underlie clinically significant pain conditions.…”