Collybolide

Last updated
Collybolide
Collybolide improved transparent.png
Names
Systematic IUPAC name
(3S,4R,4aS,5R,8R,9aR)-4-(benzoyloxy)-3-(3-furanyl)hexahydro-5-methyl-5,8-Methano-1H-pyrano[3,4-d]oxepin-1,6(5H)-dione
Other names
  • (+)-Collybolide
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
  • InChI=1S/C22H20O7/c1-22-10-14(27-21(22)25)9-15-16(22)18(29-19(23)12-5-3-2-4-6-12)17(28-20(15)24)13-7-8-26-11-13/h2-8,11,14-18H,9-10H2,1H3/t14-,15-,16-,17+,18-,22-/m1/s1
    Key: JLFUOYRQSZADHD-NVKOURDFSA-N
  • InChI=1S/C22H20O7/c1-22-10-14(27-21(22)25)9-15-16(22)18(29-19(23)12-5-3-2-4-6-12)17(28-20(15)24)13-7-8-26-11-13/h2-8,11,14-18H,9-10H2,1H3
    Key: JLFUOYRQSZADHD-UHFFFAOYSA-N
  • O(C(=O)C1=CC=CC=C1)[C@@H]2[C@@]3([C@@]4(C)C[C@@H](C[C@]3(C(=O)O[C@]2(C=5C=COC5)[H])[H])OC4=O)[H]
  • CC12CC(C(C3C1C(C(OC3=O)C4=COC=C4)OC(=O)C5=CC=CC=C5))OC2=O
Properties
C22H20O7
Molar mass 396.395 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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]

Contents

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

Collybolide is a sesquiterpene that contains a furyl-δ-lactone, a structural feature shared with the diterpene natural product salvinorin A. Salvinorin A is a hallucinogen that acts via high-potency agonism of the human kappa-opioid receptor (KOR), and collybolide's structural similarity to salvinorin A prompted a 2016 team to investigate collybolide's activity at the KOR, in the hopes of discovering a new, non-nitrogenous opioid. [1] Radioligand displacement and functional assays showed collybolide binding to (Ki = 0.9 nM) and activating the human KOR, and an in vivo assay described collybolide inhibiting chloroquine-induced itch in mice at an extremely low dose (IC50 = 0.08 mg/kg). These results attracted widespread attention in the biomedical community, as collybolide appeared to be a potent and selective KOR agonist that might be developed into a new treatment for pain or pruritus, [11] [12] lacking the adverse effects of typical mu-opioid receptor agonist pain treatments. These claims of KOR agonism also attracted the attention of the recreational psychedelic community. [13]

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. [14] [15]

Chemical synthesis

The 2022 reevaluation of collybolide's KOR activity leveraged access to both natural and unnatural enantiomers of collybolide via total synthesis. [2] [16] 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.) Collybolide scheme transparent.png
Total synthesis of collybolide (2022, Shevick et al.)

Related Research Articles

<span class="mw-page-title-main">Salvinorin A</span> Chemical compound

Salvinorin A is the main active psychotropic molecule in Salvia divinorum. Salvinorin A is considered a dissociative hallucinogen.

<span class="mw-page-title-main">Salvinorin</span> Group of chemical compounds

Salvinorins are a group of natural chemical compounds and their structural analogs. Several salvinorins have been isolated from Salvia divinorum. They are classified as diterpenoid furanolactones. Salvinorin A is a hallucinogen with dissociative effects.

<span class="mw-page-title-main">Dihydromorphine</span> Chemical compound (semi-synthetic opioid)

Dihydromorphine is a semi-synthetic opioid structurally related to and derived from morphine. The 7,8-double bond in morphine is reduced to a single bond to get dihydromorphine. Dihydromorphine is a moderately strong analgesic and is used clinically in the treatment of pain and also is an active metabolite of the analgesic opioid drug dihydrocodeine. Dihydromorphine occurs in trace quantities in assays of opium on occasion, as does dihydrocodeine, dihydrothebaine, tetrahydrothebaine, etc. The process for manufacturing dihydromorphine from morphine for pharmaceutical use was developed in Germany in the late 19th century, with the synthesis being published in 1900 and the drug introduced clinically as Paramorfan shortly thereafter. A high-yield synthesis from tetrahydrothebaine was later developed.

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.

κ-opioid receptor Protein-coding gene in the species Homo sapiens, named for ketazocine

The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.

<span class="mw-page-title-main">Erinacine</span>

Erinacines are natural substances isolated from Hericium erinaceus. They belong to the group of cyathin diterpenoids and are subjects of pharmacological research.

<span class="mw-page-title-main">Nalfurafine</span> Antipruritic drug

Nalfurafine is an antipruritic that is marketed in Japan for the treatment of uremic pruritus in individuals with chronic kidney disease undergoing hemodialysis. It activates the κ-opioid receptor (KOR) and is potent, selective, and centrally active. It is the first, and currently the only, selective KOR agonist approved for clinical use. It has also been dubiously referred to as the "first non-narcotic opioid drug" in history.

<span class="mw-page-title-main">Tifluadom</span> Pair of enantiomers

Tifluadom is a benzodiazepine derivative with an unusual activity profile. Unlike most benzodiazepines, tifluadom has no activity at the GABAA receptor, but instead is a selective agonist for the κ-opioid receptor. In accordance, it has potent analgesic and diuretic effects in animals, and also has sedative effects and stimulates appetite.

<span class="mw-page-title-main">Herkinorin</span> Chemical compound

Herkinorin is an opioid analgesic that is an analogue of the natural product salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which salvinorin A is a member.

In organic chemistry, an intramolecular Diels-Alder cycloaddition is a Diels–Alder reaction in which the diene and a dienophile are both part of the same molecule. The reaction leads to the formation of the same cyclohexene-like structure as usual for a Diels–Alder reaction, but as part of a more complex fused or bridged cyclic ring system. This reaction gives rise to various natural derivatives of decalin.

<span class="mw-page-title-main">Agonist-antagonist</span>

In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist while under other conditions, behaves as an antagonist.

<span class="mw-page-title-main">JDTic</span> Chemical compound

JDTic is a selective, long-acting ("inactivating") antagonist of the κ-opioid receptor (KOR). JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as pethidine and ketobemidone, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine. JDTic has been used to create crystal structures of KOR [ PDB: 4DJH, 6VI4​].

<span class="mw-page-title-main">Salvinorin B methoxymethyl ether</span> Chemical compound

Salvinorin B methoxymethyl ether is a semi-synthetic analogue of the natural product salvinorin A used in scientific research. It has a longer duration of action of around 2–3 hours, compared to less than 30 minutes for salvinorin A, and has increased affinity and potency at the κ-opioid receptor. It is prepared from salvinorin B. The crystal structure is almost superimposable with that of salvinorin A. Structures bound to the κ-opioid receptor have also been reported.

<span class="mw-page-title-main">Asimadoline</span> Chemical compound

Asimadoline (EMD-61753) is an experimental drug which acts as a peripherally selective κ-opioid receptor (KOR) agonist. Because of its low penetration across the blood–brain barrier, asimadoline lacks the psychotomimetic effects of centrally acting KOR agonists, and consequently was thought to have potential for medical use. It has been studied as a possible treatment for irritable bowel syndrome, with reasonable efficacy seen in clinical trials, but it has never been approved or marketed.

<span class="mw-page-title-main">ICI-199,441</span> Chemical compound

ICI-199,441 is a drug which acts as a potent and selective κ-opioid agonist, and has analgesic effects. It is a biased agonist of the KOR, and is one of a relatively few KOR ligands that is G protein-biased rather than β-arrestin-biased.

<i>Rhodocollybia maculata</i> Species of fungus

Rhodocollybia maculata, also known as the Spotted Toughshank, is a species of basidiomycete fungus in the family Marasmiaceae. It often appears in decomposing conifer duff. R. maculata is a source of collybolide, a sesquiterpenoid containing a furyl-ẟ-lactone motif reminiscent of salvinorin A.

<span class="mw-page-title-main">Capnellene</span> Chemical compound

Capnellene is a naturally occurring tricyclic hydrocarbon derived from Capnella imbricata, a species of soft coral found in Indonesia. Since the 1970s, capnellene has been targeted for synthesis by numerous investigators due to its stereochemistry, functionality, and the interesting geometry of the carbon skeleton. Many alcohol derivatives of capnellene have demonstrated potential as a chemotherapeutic agent with antibacterial, anti-inflammatory and anti-tumor properties.

<span class="mw-page-title-main">IBNtxA</span> Chemical compound

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<span class="mw-page-title-main">Buprenorphine/samidorphan</span> Combination drug formulation

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<span class="mw-page-title-main">RB-64</span> Chemical compound

RB-64 is a semi-synthetic derivative of salvinorin A. It is an irreversible agonist, with a reactive thiocyanate group that forms a bond to the κ-opioid receptor (KOR), resulting in very high potency. It is functionally selective, activating G proteins more potently than β-arrestin-2. RB-64 has a bias factor of up to 96 and is analgesic with fewer of the side-effects associated with unbiased KOR agonists. The analgesia is long-lasting. Compared with unbiased agonists, RB-64 evokes considerably less receptor internalization.

References

  1. 1 2 3 Gupta, Achla; Gomes, Ivone; Bobeck, Erin N.; Fakira, Amanda K.; Massaro, Nicholas P.; Sharma, Indrajeet; Cavé, Adrien; Hamm, Heidi E.; Parello, Joseph; Devi, Lakshmi A. (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. Bibcode:2016PNAS..113.6041G. doi: 10.1073/pnas.1521825113 . PMC   4889365 . PMID   27162327.
  2. 1 2 3 4 5 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. PMC   9335922 . PMID   35912357.
  3. ↑ Hansske, Friedrich; Paululat, Thomas; Gerlitz, Martin; Gruen-Wollny, Iris (June 9, 2005). "WO2005051376 - Arzneimittel enthaltend Collybolide". WIPO. Archived from the original on May 11, 2023. Retrieved May 11, 2023.
  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.
  5. ↑ Pascard-Billy, Claudine (1970). "X-Ray crystallographic determination of the structure of the sesquiterpenoid isocollybolide". Journal of the Chemical Society D: Chemical Communications (24): 1722a. doi:10.1039/c2970001722a. ISSN   0577-6171.
  6. ↑ Ayer, William A.; Browne, Lois M. (1981-01-01). "Terpenoid metabolites of mushrooms and related basidiomycetes". Tetrahedron. 37 (12): 2197–2248. doi:10.1016/S0040-4020(01)97979-7. ISSN   0040-4020.
  7. ↑ Pascard-Billy, Claudine (1970). "X-Ray crystallographic determination of the structure of the sesquiterpenoid isocollybolide". Journal of the Chemical Society D: Chemical Communications (24): 1722a. doi:10.1039/c2970001722a. ISSN   0577-6171.
  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)". Tetrahedron (in French). 30 (11): 1327–1336. doi:10.1016/S0040-4020(01)97243-6. ISSN   0040-4020.
  9. ↑ Fogedal, Mats; Norberg, Thomas (1986-01-01). "Deoxycollybolidol, a sesquiterpene from collybia peronata". Phytochemistry. 25 (11): 2661–2663. doi:10.1016/S0031-9422(00)84533-1. ISSN   0031-9422.
  10. ↑ Castronovo, Francesca; Clericuzio, Marco; Toma, Lucio; Vidari, Giovanni (2001-04-02). "Fungal metabolites. Part 45: The sesquiterpenes of Collybia maculata and Collybia peronata". Tetrahedron. 57 (14): 2791–2798. doi:10.1016/S0040-4020(01)00120-X. ISSN   0040-4020.
  11. ↑ Santino, Federica; Gentilucci, Luca (January 2023). "Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects". Molecules. 28 (1): 346. doi: 10.3390/molecules28010346 . ISSN   1420-3049. PMC   9822356 . PMID   36615540.
  12. ↑ Chakraborty, Soumen; Majumdar, Susruta (2021-05-11). "Natural Products for the Treatment of Pain: Chemistry and Pharmacology of Salvinorin A, Mitragynine, and Collybolide". Biochemistry. 60 (18): 1381–1400. doi:10.1021/acs.biochem.0c00629. ISSN   0006-2960. PMC   7982354 . PMID   32930582.
  13. ↑ "Anyone know about collybia maculata?". Reddit. October 5, 2020. Archived from the original on May 10, 2023. Retrieved May 10, 2023.
  14. ↑ 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". European Journal of Medicinal Chemistry. 243: 114785. doi:10.1016/j.ejmech.2022.114785. ISSN   0223-5234.
  15. ↑ 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". Molecules. 28 (1): 346. doi:10.3390/molecules28010346. ISSN   1420-3049. PMC   9822356 . PMID   36615540.
  16. ↑ "Synthesis and Reevaluation of (+)- and (−)-Collybolide as kappa-Opioid Receptor Agonists". Synfacts. 18 (11): 1251. October 18, 2022. doi:10.1055/s-0041-1738630. ISSN   1861-1958.
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