EPIBATIDINE
The toxicology and prospective pharmacology of a toxin
derived from Epipedobates anthoyi.
By: Kriti Mishra, Aaron Marks, Bikal Wagle, & Carlos Garcia
What is Epibatidine?
• A toxic substance derived
from the skin of the
poison dart frog,
Epipedobates anthoyi.
• Ecuadorian natives use
the toxin on their darts
to kill big game.
• It was discovered by John
Daly in 1974.
• It has stronger analgesic
properties than
morphine.
Why Epibatidine?
• Morphine is an opioid analgesic used in the medical
field with a high potential for addiction, psychological
dependence, and tolerance.
• Epibatidine binds to a different receptor than
morphine.
• Epibatidine is a strong contender to take the place of
morphine without being addictive.
• On the other hand, the effective dose of epibatidine is
very close to the lethal dose. Narrow safety margin!
• Less lethal derivatives of epibatidine are being
researched.
What will you learn?
• Mechanism of action
• Past research
• Implications of the research conducted
• Future research
Don’t even think
about touching
me.
DATA: Where does Epibatidine Bind?
• Epibatidine does not bind to
opioid receptors like morphine.
• Epibatidine has a Ki of 0.12 (high
binding affinity) for nicotinic
acetylcholine receptors
(nAChr).
• nACHr’s are specific receptors of
skeletal muscle
DATA: Where does Epibatidine Bind?
• Naloxone is an antagonist of
opioid receptors.
• When mice were injected with
BOTH naloxone and epibatidine,
the mice were fully influenced by
the effects of epibatidine.
• KEY POINT: Epibatidine does not
bind to opioid receptors.
DATA: Straub Reaction Tests
• In a Straub reaction test, the
tail of an animal becomes
rigid in an S-shaped curve in
response to a neuronal
effector.
• The left column epibatidine
requires a much smaller
administered dose (mg/kg)
to elicit Straub response
compared to morphine.
• The right column indicates
that epibatidine has a very
low affinity for opioid
receptors.
DATA: Hot Plate Analgesia Tests
• Hot plate analgesia is a behavioral model of
nociception.
• Nociception is the perception of painful stimuli.
• Behaviors such as jumping and hind paw-licking are
elicited following placing a live sample with a noxious
thermal stimulus.
• Mice injected with epibatidine stay longer on the
hot plates due to a greater analgesic effect than
mice injected with morphine.
• Epibatidine was reported to be a 200 times
more potent analgesic than morphine.
DATA: CNS and PNS Specificity
• In vivo testing with mice models shows that
epibatidine binds to the Central Nervous System
(CNS) AND the Peripheral Nervous System (PNS).
1.CNS: Epibatidine binds to nAChr’s of the CNS
tissue and elicits an analgesic effect.
• This has been hypothesized that Epibatidine binding induces neurotransmitter
release of dopamine and norepinephrine.
2.PNS: Epibatidine ALSO simultaneously binds to
nAChr’s of the the neuromuscular junction of
skeletal muscle causing muscular PARALYSIS
(Sullivan et al. 1994).
What are the Upsides?
• Epibatidine has a much stronger analgesic effect
than opioids like morphine and codeine.
• Epibatidine binds nAChr’s in the central nervous
system tissue causing analgesic effects.
• It does not bind to opioid receptors.
What are the Downsides?
• Epibatidine is too toxic for clinical use.
• Epibatidine binding to the peripheral nervous
system, specifically skeletal muscle nAChr’s,
causes paralysis.
Implications:
• Epibatidine medicinal research is still very promising!
• The idea: Find the pharmacophore of the molecule, and
modify it so that is safe for human consumption while
still maintaining is powerful analgesic properties by
targeting only the CNS.
• Pharmacophore: the region of the molecule that has an
active effect in binding with the receptor.
• A new class of analgesic drugs can be developed that
mitigate the negative side effects of opioid analgesics
while having superior analgesic properties.
The Future of Epibatidine:
• A pharmacophore called ABT-594 was discovered by
Abbott industries.
• ABT-594 is also known as Tebanicline or Ebanicline.
• It is a non-opioid drug and does not produce the
negative side-effects of morphine: respiratory
depression, tolerance, and addiction in a mouse model.
• ABT-594 is effective against acute, chronic, and
neuropathic pain.
• It selectively inhibits afferent
pain signal transmission without
other sensory modalities such as
touch.
The Future of ABT-594:
• ABT-594 seems to be a miracle replacement for morphine
without the ill-effects of morphine.
• Nicotine is very addictive and is similar in structure to ABT-594.
• The presence of addictive effects of ABT-594 in human models
are unknown.
• Mouse physiology is certainly different from human; there have
been accounts of promising
drugs that fail in human trials.
• Future research needs to be
conducted to find the possible
addictive effects of ABT-594
in humans.
Summary:
• WHAT?
• Epibatidine
• WHERE?
• Found on the skin of a poison dart frog found in the
Ecuadorian Forests
• HOW?
• Binds to nAChr’s and provides analgesic properties
stronger than that of morphine without addictive
effects
References:
• Badio, Barbara, and John Daly. "Epibatidine, a Potent Analgetic and Nicotinic Agonist."
Molecular Pharmacology 45 (1994): 563-569.
• Bannon, A.W., Decker, M.W., Holladay, M. W., Curzon, P>, Donnelly-Roberts, D.,Porsolt,
R.D., Williams, M., Arneric, S.P. Broad-Spectrum, Non-Opioid Analgesic Activity by
Selective Modulation of Neuronal Nicotinic Acetylcholine Receptors. Science 2 January
1998: vol. 279, No. 5347, pp. 77-80.
• Bonhaus, D. W., Bley, K. R., Broka, C. A., Fontana, D. J., Leung, E., Lewis, R., ... & Wong, E.
H. (1995). Characterization of the electrophysiological, biochemical and behavioral
actions of epibatidine. Journal of Pharmacology and Experimental Therapeutics, 272(3),
1199-1203.
• Spande, T. F., Garraffo, H. M., Edwards, M. W., Yeh, H. J., Pannell, L., & Daly, J. W. (1992).
Epibatidine: a novel (chloropyridyl) azabicycloheptane with potent analgesic activity from
an Ecuadoran poison frog. Journal of the American Chemical Society, 114(9), 3475-3478.
• Strong, Suzanne. "Altering Chemistry: Epibatidine a Novel Alkaloid."Sjbr/strong/1998. 1
Jan. 1998. Web. 16 Apr. 2015.
<http://wwwchem.csustan.edu/chem4400/sjbr/strong98.htm>.
• Sullivan JP, Decker MW, Brioni JD, Roberts-Donnelly D, Anderson DJ, Bannon A,
Gopalakrishnan M, Piattoni-Kaplan M, Adams P, Buckley MJ, Kang CH, Williams M,
Arneric SP (1994) Pharmacological properties of (±)-epibatidine: A potent nicotinic
acetylcholine receptor ligand. J Pharmacol Exp Ther 271:624–631
• Traynor, J. R. (1998). Epibatidine and pain. British journal of anaesthesia, 81(1), 69-76.