Phantasmidine is a toxic substance derived from the Ecuadorian poisonous frog Anthony's poison arrow frog (Epipedobates anthonyi), more commonly known as the “phantasmal poison frog”.[2] It is a nicotinic agonist, meaning it binds to nicotinic receptors in the body and mimics the effects of the neurotransmitter acetylcholine. This causes the stimulation of the body's parasympathetic nervous system, which induces many inhibitory behaviors in the body such as decreased heart rate.
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| Preferred IUPAC name
(2aS,4aR,9aR)-7-Chloro-1,2,2a,3,4,4a-hexahydrocyclobuta[4′,5′]pyrrolo[3′,4′:4,5]furo[2,3-b]pyridine | |
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3D model (JSmol)
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PubChem CID
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CompTox Dashboard (EPA)
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| Properties[1] | |
| C11H11ClN2O | |
| Molar mass | 222.67 g·mol−1 |
| Appearance | Crystalline solid |
| Density | 1.5±0.1 g/cm3 |
| Boiling point | 358.9±42.0°C at 760 mmHg |
| Hazards | |
| Flash point | 170.9±27.9°C |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Phantasmidine is characterized in the same class as epibatidine, which is a similar nicotinic acetylcholine agonist derived from a poisonous frog species. Some synthetic processes can even generate phantasmidine using epibatidine as a starting reagent. Epibatidine and epibatidine-related compounds have an LD50 of around 4 μg in mice;[3] however, the exact LD50 of phantasmidine is not known.
-Epibatidine_Structural_Formulae_V.1.svg)
Phantasmidine may find application as an analgesic or muscle relaxant.
Synthesis
editMultiple syntheses of phantasmidine have been proposed, some of which have been included below. The general mechanism for the synthesis of phantasmidine is shown below.[4]
In the general reaction mechanism, 1,2-bis(trimethylsilyloxy)cyclobutene is reacted with the intermediate to form the second product in 85% yield. This is then run under basic conditions to produce an intramolecular aldol reaction followed by an intramolecular nucleophilic aromatic substitution, leading to the lactam product in 46% yield. The final step involves reacting this product with BH3 in THF, then reacting the product with piperazine in MeOH at reflux.
6-chloro-2-fluoro-3-pyridineacetamide is used as an intermediate in most syntheses, which is then reacted through these three general steps to produce phantasmidine. The structure of this intermediate is shown as the starting reagent in the general reaction mechanism above.
Modern synthetic procedures, however, generally begin with 2-chloro-6-fluoropyridine as the starting reagent, due to its commercial availability. This is then converted in several steps to the 6-chloro-2-fluoro-3-pyridineacetamide intermediate. The overall yield of (±) phantasmidine for the modern synthesis shown below is 8% (Zhou, Q. and B. B. Snider 528).
Chemical Properties
edit(±) Phantasmidine is a crystalline solid. The syntheses of phantasmidine result in racemic mixtures, making it difficult to synthesize an individual enantiomer of phantasmidine. However, through the utilization of HPLC, the individual enantiomers can be separated.[5] HPLC thereby allows for the classification and characterization of (-) and (+) phantasmidine individually.
_and_(%2B)_Phantasmidine.png)
The assignation for the 1H NMR shift values of (-) phantasmidine are listed below[6] (Fitch et al.).
| H Position | ∂ Value (ppm) | J Value (Hz) |
|---|---|---|
| 2 | 4.24 | 7.5, 7.0 |
| 3α | 2.22 | ≈11, 3.4 - 7.1 |
| 3β | 1.74 | – |
| 4α | 2.63 | 11.5 |
| 4β | 2.38 | 11.9 |
| 10 | 7.02 | 7.7 |
| 11 | 7.70 | 7.7 |
| 13 | 4.08 | 6.8 |
| 14α | 3.92 | 7.2 |
| 14β | 3.69 | 12.5 |
The characterized data gathered from the IR spectrum for (-) phantasmidine is shown in the table below (Fitch et al. 17) (Fitch et al. 336-337).
| Absorption (cm−1) | Functional Group Indicated |
|---|---|
| 3055 | 5- and 6-membered ring C-H stretch |
| 2997 | Cyclobutane C-H |
| 2960 | Aromatic C-H |
| | C=C stretch | |
| | C=N absorption | |
| 1264 | C-O absorption adjacent to pyridine C=N |
Biological Effects
editMetabolism
editPhantasmidine is a nicotinic agonist that acts at acetylcholine receptors. It mimics the effects of acetylcholine on the body's neuronal-based nervous systems (both the central nervous system [CNS] and the peripheral nervous system [PNS]) and the muscle-based nervous system (the somatic nervous system).
Mechanism of Action
editNicotinic acetylcholine receptors in general comprise a sub-section of the family of ligand-gated ion channels, of which ions such as Ca+2, Na+, and K+ are permeable to the barrier.[7] Phantasmidine is selective for nicotinic acetylcholine receptors (nAChR) containing β4 subunits; however, responses in neuromuscular nAChR (such as β1-containing receptors) and β2-containing neuronal receptors (such as K-177 cells) are also elicited, albeit to a lesser degree (Fitch et al. 331-337).
Studies conducted in mice have proved useful in showing the interaction and relationship of nAChR α- and β-subunits to the body's processes and interaction with this toxin. In particular, α3 and β4 nAChR subunits have been shown to play a role in ganglionic transmission, indicating they play a role in the stimulation of either the parasympathetic nervous system (as an agonist) or the sympathetic nervous system.
- When the β4 subunit was eliminated in mice, the mice were resistant to nicotine-induced seizures and displayed reduced nicotine withdrawal (when compared with wild mice) (Fitch et al. 331-337).
- α4 subunits have been proved to play an important role in preserving the body's nociceptive response (Zhou 120 – 123); when the body experiences pain, the receptors involved in this pathway will signal the autonomic nervous system and create a subsequent sensation of pain. Due to the continuous influx of positive charge (as a result of the depolarization of the cell), the cell will continue to send action potentials, causing the brain to receive constant pain signals.
- β2 subunits have been indicated to play a role in the body's learning, memory, and addiction pathways (Zhou 120 – 123).
The table below[8][9] summarizes the types of cells that phantasmidine affects as well as the resultant behavior exhibited in the listed species. The depolarization of a cell results from the activation of a cation-permeable membrane, which causes an influx of Ca+2 into the cell. This influx of positive charge induces the release of acetylcholine into the body to interact with the parasympathetic nervous system. This, in turn, causes the inhibitory responses exhibited.
| Species | Receptor Type | Activity | Cells Affected | Cellular Response | Physiological Response |
|---|---|---|---|---|---|
| Rat | α3β4 | Active | HEK cells | Membrane depolarization | Stimulation of PNS |
| Rat | α4β2 | Inactive | HEK cells | Membrane depolarization | Pain Response |
| Rat | α4β4 | Active | HEK cells | Membrane depolarization | Pain Response; Stimulation of PNS |
| Rat | α3β4 | Active | HEK cells | Membrane depolarization | Stimulation of PNS |
| Human | α1β1γ∂ | Inactive | TE-671 cells | Membrane depolarization | Stimulation of PNS |
| Human | α4β2 | Inactive | K-177 cells | Membrane depolarization | Pain Response |
| Human | α3β4 | Active | IMR-32 cells | Membrane depolarization | Stimulation of PNS |
| Human | α3β4 | Active | SH-SY5Y cells | Membrane depolarization | Stimulation of PNS |
Toxicity and Treatment
editNot much about the exact toxicity of phantasmidine is known; however, epibatidines in general are 200 times more potent than morphine (Riley 21). Phantasmidine interacts with the body's stimulation of the parasympathetic nervous system, making it a dangerous inhibitory poison. Symptoms of phantasmidine poisoning may include decreased heart rate, continuous sensations of pain, coma, and (in larger doses) death.
A plausible antidote for phantasmidine poisoning would be mecamylamine, a nAChR antagonist (Zhou 120 – 123). Other nAChR antagonists may serve as effective antidotes for this particular type of poisoning, as they would block nAChR to prevent the acetylcholine agonist from binding to the acetylcholine receptors.
Analgesics
editNicotinic agonists in general have proved to be useful analgesics in treating disorders that respond to nAChR (Fitch et al. 1-17) (Zhou 120-123). For example, phantasmidine or phantasmidine-derivatives are being tested for their potential use as short-acting muscle relaxants. They are also currently being researched as potential analgesics for the treatment of:
- Neurodegenerative disorders (such as dementia caused by Alzheimer's disease)
- Myasthenia Gravis
- Tobacco dependence
- Glaucoma
- Tourette syndrome
- Cardiovascular disorders (such as hypertension)
- Psychiatric disorders (such as schizophrenia)
- Pain
- Epilepsy
Such treatments can be administered parenterally (intravenously, intradermally, intramuscularly) or through inhalation of a pharmaceutically-composed aerosol.
References
edit- ^ "Phantasmidine". ChemSpider. Royal Society of Chemistry. Retrieved 30 April 2015.
- ^ Fitch, Richard W.; Spande, Thomas F.; Garraffo, H. Martin; Yeh, Herman J. C.; Daly, John W. (26 March 2010). "Phantasmidine: an Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates Anthonyi". Journal of Natural Products. 73 (3): 331–337. doi:10.1021/np900727e. PMC 2866194. PMID 20337496.
- ^ Riley, Darren Lyall. "Synthesis of Amphibian Indolizidine Alkaloids and Related Compounds from Enaminone Precursors" (PDF). University of the Witwatersrand. Retrieved 27 April 2015.
- ^ Zhou, Q.; Snider, B.B. (22 December 2010). "Synthesis of Phantasmidine". Organic Letters. 13 (3): 526–529. doi:10.1021/ol102929m. PMC 3031734. PMID 21175153.
- ^ Zhou, Q.; Snider, BB (7 August 2013). "Mosher's Amide-Based Assignment of the Absolute Configuration of Phantasmidine". Heterocycles. 88 (1): 779–787. doi:10.3987/COM-13-S(S)45.
- ^ Fitch, Richard W.; et al. (24 October 2013). "Nicotinic Acetylcholine Receptor Agonists". United States Patent Application Publication. 1 (12/583, 420): 1–17. Retrieved 29 April 2015.
- ^ Zhou, Quan (February 2012). "Syntheses of Vibralactones, Phantasmidine, and Pharnafungins Ring System". UMI Dissertation Publishing. Brandeis University Department of Chemistry (3494457): 120–123. Retrieved 29 April 2015.
- ^ The European Bioinformatics Institute, Wellcome Trust Genome Campus. "Compound Report Card: Phantasmidine". ChEMBL. European Molecular Biology Lab. Retrieved 27 April 2015.
- ^ PubChem. "Phantasmidine". PubChem. National Institutes of Health. Retrieved 1 May 2015.