Part of OutCo's science talks, this presentation is focused the history and bioactivity of synthetic cannabinoids.

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Synthetic Cannabinoids
Dr. Markus Roggen
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1.Same but different
2.The opioid epidemic
3.The dawn of synthetic cannabinoids
4.The Good
5.The Bad
6.The Ugly
7.The Future 2
Abstract

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Same but different
How small changes in molecular structure have huge effects

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Molecular structure has a huge effect on how
molecules interact with the human body. Small
changes in stereochemistry, functional groups or
carbon backbone will change the effect.
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Same but Different

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Vanilla
• Second most expensive spice
• Worlds favored flavoring
• 95% of all “vanilla” products use synthetic vanillin
• Real vanilla better for cookies, syn. vanillin for baking
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Same but Different
Real Fake
Plus hundreds of other compounds

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Total Synthesis vs. Semisynthesis
• Taxol is an anticancer drug
isolated from Pacific Yew
• First total synthesis by Holton:
46 linear steps
• Semisynthesis by Holton with
80% yield from European Yew
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Same but Different

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The Opioid Epidemic
A Case Study

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• Heroin acts on opioid receptor
• Relieves pain
• Produces feeling of euphoria
• Highly addictive
• High doses can depress breathing
• Naxloxone reverses effects of opioid overdose
• Has stronger affinity for opioid receptor
• Works within 2 minutes of injection
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The Opioid Epidemic

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• Fentanyl is a synthetic opioid, prescribed by doctors
for chronic pain
• Higher potency increases risk of overdose
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The Opioid Epidemic

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Synthetic Cannabinoids
Shout out to Clemson

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• Professor Emeritus, Organic Chemistry, Clemson
University
• Began in 1984 to synthesis novel cannabinoids
• Focused on targeting endocannabinoid receptors
• For multiple sclerosis, HIV, chemoterapy, …
• Over 450 synthetic cannabinoids developed
• First used as marijuana alternatives in Germany in
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John William Hoffman

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• Professor, Department of Medicinal Chemistry,
Northeastern University
• Study of interactions ‘cannabinoid-like’ molecules
with CB1 & CB2 receptor
• Design and synthesis of novel therapeutically useful
drugs for pain, appetite and central nervous system
diseases
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Alexandros Makriyannis

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• Professor, Department of Medicinal Chemistry,
Hebrew University of Jerusalem
• First to isolate, characterize and synthesis of THC
• Isolated and identified endocannabinoids
• HU-210
• Promotes proliferation, but not differentiation, of
hippocampal neural stem and progenitor cells
• Indication of antianxiety and antidepressant effects
• Implicated in inflammation prevention due to amyloid
beta proteins involved in Alzheimer’s
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Raphael Mechoulam

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• Synthesized in the 1970s and 1980s
• Recently discovered in recreational drugs
• CP 55,940
• Widely used cannabinoid research tool
• Neuroprotective by reducing intracellular calcium
release
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Pfizer

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• Molecules that target CB1 & CB2 receptors
• No precedent in scientific literature
• Appear to be rationally designed
• Little to no information about pharmacology and
toxicology
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Designer Cannabinoids

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• Agonist binds to receptor: Key for the lock
• Full: Copy of key
• Partial: Lock Pick
• Inverse: Opposite effect of normal
• Antagonist blocks others from binding: Putty for lock
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Terms and Conditions

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• THC: Partial agonist to CB1 & CB2
• CBD: Antagonist for CB1 & CB2
• 2-AG: Full agonist for CB1
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Terms and Conditions

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• All claims made are ’soft’
• Didn’t find a drug that is FDA approved
• Most studies are in animal models or in vitro
• Therefore not directly applicable to humans
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Terms and Conditions

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The Good
Cannabinoid Analogs in Medical Research

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• Full CB agonist
• Potent analgesic (painkiller)
• Prevent inflammation caused by amyloid beta proteins
involved in Alzheimer’s disease
• Prevent cognitive impairment, loss of neuronal markers
• Reduces voluntary wheel running in mice
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WIN 55,212-2

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• Potent CB2 agonist
• 200x more selective for CB2 over CB1
• Not psychoactive as CB2 selective
• Prevent inflammation caused by amyloid beta
proteins involved in Alzheimer’s disease
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JWH-133

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• Prof. Bob Moore II, University of Tenesee
• CB2 inverse agonist
• In pre-clinical development for treatment of
neurodegenerative disorders and traumatic brain
injury
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SMM-189
doi: 10.1002/prp2.159

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The Bad
Bath Salts and others

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• Anti-obesity drug / appetite suppressant
• Inverse agonist for CB1
• Approved in 2006 (EU), first of its class
• Withdrawn in 2008
• Risk of serious psychiatric problems
• 10% experience depressive disorders
• 1% suicidal ideation
• Additionally: nausea, upper respiratory tract infections,
anxiety, insomnia, diarrhea, vomiting, …
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Rimonabant, Sanofi-Aventis

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• Full agonist for CB1 & CB2
• Similar effects to THC, but 5x greater
• Death linked to JWH-018 by drug toxicity and organ
failure
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JWH-018

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The Ugly
“The is some weird shit, man”

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• “Unnatural” enantionmer of HU-210
• Not a CB agonist
• NMDA antagonist
• Anesthetic effect like ketamine or synthetic opioids
• No cannabis-like effects
• But anticonvulsant and neuroprotective
• Studied for treating head injury, stroke, or cancer
• Currently in Phase I for treating brain cancer
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Dexanabinol

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• Patented by Mark Scialdone, PhD
• He reports similar ‘High’ as THC
• No further clinical study beyond his own consumption
• He hydrogenated cannabis extract, then consumed it
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Hydrogenated Cannabinoids

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The Future
What is there to come?

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• Protecting Groups can be used to prevent
metabolizing of compound
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Protecting Groups

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• Most interesting sites for modification
• C-11 methyl group
• C5 side chain
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Active Sites

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• Different cannabinoid inspired structures as starting
point for active compound
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Different Cannabinoid Scaffold