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
| |
Identifiers | |
3D model (
JSmol)
|
|
ChemSpider | |
PubChem
CID
|
|
| |
| |
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]
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.
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]
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.
{{
cite web}}
: CS1 maint: bot: original URL status unknown (
link)
{{
cite web}}
: CS1 maint: bot: original URL status unknown (
link)
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
| |
Identifiers | |
3D model (
JSmol)
|
|
ChemSpider | |
PubChem
CID
|
|
| |
| |
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]
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.
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]
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.
{{
cite web}}
: CS1 maint: bot: original URL status unknown (
link)
{{
cite web}}
: CS1 maint: bot: original URL status unknown (
link)