Chemistry:Collybolide

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Template:Chemical infobox Collybolide is a secondary metabolite of the Rhodocollybia maculata mushroom, a basidiomycete fungus that grows on rotting conifer wood. It was previously believed to be a potent and selective kappa-opioid receptor agonist.[1] However, a total synthesis and independent biological assay determined that collybolide neither excites nor suppresses kappa-opioid receptor signaling.[2] Collybolide is unlikely to be psychoactive, although it has been shown to inhibit L-type calcium channels in isolated rat aorta.[3]

History

Collybolide was first isolated from R. maculata in 1911,[4][5][6] but its structure remained unsolved until the 1970s, when X-ray crystallography yielded the structure of a collybolide epimer, isocollybolide,[7] and 1H and 13C NMR elucidated the structure and relative stereochemistry of collybolide.[8] Importantly, early reports were unable to confidently assign the absolute configuration of collybolide; a 1986 isolation of a collybolide congener noted that the absolute configuration of the series "remains to be determined",[9] and a 2001 circular dichroism study was only able to tentatively infer which enantiomer naturally occurred based on density functional theory calculations.[10] A 2016 report claimed to have conclusively assigned the absolute configuration of collybolide by X-ray crystallography,[1] but a following 2022 report noted that the Flack parameter accompanying the 2016 crystal structure was inconclusive,[2] and could not be used to confidently assign its absolute stereochemistry.

Purported kappa-opioid receptor agonism

Independent chemical synthesis and biological assay of collybolide in 2022 found, that it was devoid of opioid activity.[2] Radioligand displacement assays showed only weak (Ki = 794 nM) binding of collybolide to the human KOR, and functional assays showed that collybolide does not activate KOR signaling at concentrations up to 10 μM (measured by [35S]GTPγS binding, cAMP accumulation, and beta-arrestin recruitment assays). Shevick et al. note the presence of surface-modifying agents in the 2016 assay procedures, in addition to low percent stimulation in the 2016 [35S]GTPγS assay, that may have caused noise in the data to be mistaken as signal.[2] The source of the false positive result for KOR agonism in the 2016 study has yet to be rigorously identified. However, the findings and conclusions of the 2022 study – that collybolide was incorrectly assigned as a KOR agonist – explain why no credible reports of collybolide's psychoactivity have surfaced.[11][12]

Chemical synthesis

The 2022 reevaluation of collybolide's KOR activity leveraged access to both natural and unnatural enantiomers of collybolide via total synthesis.[2][13] Key features of the synthesis included an enantioselective Diels-Alder reaction using the Hayashi-Jørgensen proline organocatalyst, and an enamine [3,3]-sigmatropic rearrangement to stereoselectively install a late-stage benzoyloxy (BzO) group.

Total synthesis of collybolide (2022, Shevick et al.)

References

  1. ↑ 1.0 1.1 Gupta, Achla; Gomes, Ivone; Bobeck, Erin N.; Fakira, Amanda K.; Massaro, Nicholas P.; Sharma, Indrajeet; Cavé, Adrien; Hamm, Heidi E. et al. (9 May 2016). "Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity". Proceedings of the National Academy of Sciences 113 (21): 6041–6046. doi:10.1073/pnas.1521825113. PMID 27162327. Bibcode: 2016PNAS..113.6041G. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Shevick, Sophia L.; Freeman, Stephan M.; Tong, Guanghu; Russo, Robin J.; Bohn, Laura M.; Shenvi, Ryan A. (27 July 2022). "Asymmetric Syntheses of (+)- and (−)-Collybolide Enable Reevaluation of kappa -Opioid Receptor Agonism". ACS Central Science 8 (7): 948–954. doi:10.1021/acscentsci.2c00442. PMID 35912357. 
  3. ↑ Hansske, Friedrich; Paululat, Thomas; Gerlitz, Martin; Gruen-Wollny, Iris (June 9, 2005). "WO2005051376 - Arzneimittel enthaltend Collybolide". https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005051376. 
  4. ↑ Goris, A.; Mascre, M. (1911). "Sur la composition chimique de quelques Champignons superieurs". Comptes rendus hebdomadaires des séances de l'Académie des sciences 153: 1082–1084. https://archive.org/details/comptes-rendus-hebdomadaires-des-seances-...-academie-des-bpt-6k-3106p/page/n1/mode/2up. 
  5. ↑ Pascard-Billy, Claudine (1970). "X-Ray crystallographic determination of the structure of the sesquiterpenoid isocollybolide" (in en). Journal of the Chemical Society D: Chemical Communications (24): 1722a. doi:10.1039/c2970001722a. ISSN 0577-6171. http://xlink.rsc.org/?DOI=c2970001722a. 
  6. ↑ Ayer, William A.; Browne, Lois M. (1981-01-01). "Terpenoid metabolites of mushrooms and related basidiomycetes" (in en). Tetrahedron 37 (12): 2197–2248. doi:10.1016/S0040-4020(01)97979-7. ISSN 0040-4020. https://www.sciencedirect.com/science/article/pii/S0040402001979797. 
  7. ↑ Pascard-Billy, Claudine (1970). "X-Ray crystallographic determination of the structure of the sesquiterpenoid isocollybolide" (in en). Journal of the Chemical Society D: Chemical Communications (24): 1722a. doi:10.1039/c2970001722a. ISSN 0577-6171. http://xlink.rsc.org/?DOI=c2970001722a. 
  8. ↑ Bui, A. -M.; Cavé, A.; Janot, M. -M.; Parello, J.; Potier, P.; Scheidegger, U. (1974-01-01). "Isolement et analyse structurale du collybolide, nouveau sesquiterpene extrait de Collybia maculata alb. et sch. ex fries (basidiomycetes)" (in fr). Tetrahedron 30 (11): 1327–1336. doi:10.1016/S0040-4020(01)97243-6. ISSN 0040-4020. https://www.sciencedirect.com/science/article/pii/S0040402001972436. 
  9. ↑ Fogedal, Mats; Norberg, Thomas (1986-01-01). "Deoxycollybolidol, a sesquiterpene from collybia peronata" (in en). Phytochemistry 25 (11): 2661–2663. doi:10.1016/S0031-9422(00)84533-1. ISSN 0031-9422. https://www.sciencedirect.com/science/article/pii/S0031942200845331. 
  10. ↑ Castronovo, Francesca; Clericuzio, Marco; Toma, Lucio; Vidari, Giovanni (2001-04-02). "Fungal metabolites. Part 45: The sesquiterpenes of Collybia maculata and Collybia peronata" (in en). Tetrahedron 57 (14): 2791–2798. doi:10.1016/S0040-4020(01)00120-X. ISSN 0040-4020. https://www.sciencedirect.com/science/article/pii/S004040200100120X. 
  11. ↑ Khan, Md Imdadul H.; Sawyer, Benjamin J.; Akins, Nicholas S.; Le, Hoang V. (2022-12-05). "A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse" (in en). European Journal of Medicinal Chemistry 243: 114785. doi:10.1016/j.ejmech.2022.114785. ISSN 0223-5234. PMID 36179400. https://www.sciencedirect.com/science/article/pii/S0223523422006870. 
  12. ↑ Santino, Federica; Gentilucci, Luca (January 1, 2023). "Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects" (in en). Molecules 28 (1): 346. doi:10.3390/molecules28010346. ISSN 1420-3049. PMID 36615540. 
  13. ↑ "Synthesis and Reevaluation of (+)- and (−)-Collybolide as kappa-Opioid Receptor Agonists" (in en). Synfacts 18 (11): 1251. October 18, 2022. doi:10.1055/s-0041-1738630. ISSN 1861-1958. http://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1738630. 



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