Dehydrocorybulbine

Dehydrocorybulbine
Names
	IUPAC name 3-Hydroxy-2,9,10-trimethoxy-13-methyl-7,8,13,13a-tetradehydroberbin-7-ium
	Systematic IUPAC name 3-Hydroxy-2,9,10-trimethoxy-13-methyl-5,6-dihydro-7λ5-isoquinolino[3,2-a]isoquinolin-7-ylium
Identifiers
CAS Number	59870-72-3 [[1]];
3D model (JSmol)	Interactive image;
ChEMBL	ChEMBL3343658;
ChemSpider	4475496;
PubChem CID	5316439;
CompTox Dashboard (EPA)	DTXSID301045755 ;
	InChI InChI=1S/C21H21NO4/c1-12-14-5-6-18(24-2)21(26-4)16(14)11-22-8-7-13-9-17(23)19(25-3)10-15(13)20(12)22/h5-6,9-11H,7-8H2,1-4H3/p+1 Key: XWCVASCMRTXXRY-UHFFFAOYSA-O;
	SMILES O(c4cc3c2c(c1ccc(OC)c(OC)c1c[n+]2CCc3cc4O)C)C;
Properties
Chemical formula	C21H22NO4+
Molar mass	352.40 g/mol
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Dehydrocorybulbine (DHCB) is a protoberberine isoquinoline alkaloid isolated from the tuber of Corydalis yanhusuo. It is being studied for its potential analgesic properties, particularly for neuropathic and inflammatory pain.

Its primary analgesic mechanism is antagonism of the dopamine D2 receptor (D2R). Unlike opioid analgesics, preclinical studies found that DHCB does not induce antinociceptive tolerance.^[2] It also possesses a distinct anti-neuroinflammatory mechanism by inhibiting purinergic P2X4 receptor (P2X4R).^[3]

Pharmacology

Dopamine D2 receptor antagonism

The primary mechanism of action for DHCB's analgesic effect is antagonism of the dopamine D2 receptor (D2R). A 2014 study in Current Biology identified DHCB as the component of Corydalis extract responsible for this effect. The study confirmed this mechanism by demonstrating that DHCB's analgesic properties were absent in D2 receptor knockout (KO) mice.

This D2-based mechanism is a significant finding, as it is non-opioid and, as the study proved, "causes no antinociceptive tolerance". This differentiates it from traditional opioid pain relievers, which typically lose efficacy over time and lead to dependence. This finding corrected earlier hypotheses that had suggested the dopamine D1 receptor was the primary target.

Anti-neuroinflammatory mechanism

In addition to its dopaminergic activity, DHCB possesses a distinct anti-neuroinflammatory mechanism relevant to neuropathic pain. A 2019 study found that in preclinical models of spinal cord injury (SCI), DHCB provided pain relief by mitigating the upregulation of the purinergic P2X4 receptor (P2X4R).

P2X4Rs are primarily expressed on spinal microglia and are key mediators of neuropathic pain signaling following neuronal injury. The study found that DHCB's inhibition of P2X4R upregulation was associated with a reduction in the release of pro-inflammatory cytokines, including interleukin-1𝛽 (IL-1𝛽) and interleukin-18 (IL-18).

References

^ "KNApSAcK Metabolite Information - 59870-72-3". www.knapsackfamily.com.
^ Zhang, Yan; Wang, Chaoran; Wang, Lien; Parks, Gregory Scott; Zhang, Xiuli; Guo, Zhimou; Ke, Yanxiong; Li, Kang-Wu; Kim, Mi Kyeong; Vo, Benjamin; Borrelli, Emiliana; Ge, Guangbo; Yang, Ling; Wang, Zhiwei; Garcia-Fuster, M. Julia (2014-01-20). "A novel analgesic isolated from a traditional Chinese medicine". Current biology: CB. 24 (2): 117–123. doi:10.1016/j.cub.2013.11.039. ISSN 1879-0445. PMC 3912990. PMID 24388848.
^ Wang, Zhongwei; Mei, Wei; Wang, Qingde; Guo, Rundong; Liu, Peilin; Wang, Yuqiang; Zhang, Zijuan; Wang, Limin (2019-02-28). "Role of Dehydrocorybulbine in Neuropathic Pain After Spinal Cord Injury Mediated by P2X4 Receptor". Molecules and Cells. 42 (2): 143–150. doi:10.14348/molcells.2018.0028. ISSN 0219-1032. PMC 6399007. PMID 30622226.

[1] "KNApSAcK Metabolite Information - 59870-72-3". www.knapsackfamily.com.

[2] Zhang, Yan; Wang, Chaoran; Wang, Lien; Parks, Gregory Scott; Zhang, Xiuli; Guo, Zhimou; Ke, Yanxiong; Li, Kang-Wu; Kim, Mi Kyeong; Vo, Benjamin; Borrelli, Emiliana; Ge, Guangbo; Yang, Ling; Wang, Zhiwei; Garcia-Fuster, M. Julia (2014-01-20). "A novel analgesic isolated from a traditional Chinese medicine". Current biology: CB. 24 (2): 117–123. doi:10.1016/j.cub.2013.11.039. ISSN 1879-0445. PMC 3912990. PMID 24388848.

[3] Wang, Zhongwei; Mei, Wei; Wang, Qingde; Guo, Rundong; Liu, Peilin; Wang, Yuqiang; Zhang, Zijuan; Wang, Limin (2019-02-28). "Role of Dehydrocorybulbine in Neuropathic Pain After Spinal Cord Injury Mediated by P2X4 Receptor". Molecules and Cells. 42 (2): 143–150. doi:10.14348/molcells.2018.0028. ISSN 0219-1032. PMC 6399007. PMID 30622226.

[2]

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