Download 11/5/2014 Cannabinoids Activate CB Receptors 

11/5/2014
Cannabinoids Activate CB Receptors Phytocannabinoids
Plant derived – at least 85 identified to‐date
Synthetic cannabinoids
Include dronabinol (THC) and analogs
Endocannabinoids
Endogenous compounds (produced within the body)
Phytocannabinoids
At least 85 cannabinoids present in female Cannabis plants
At least 85 cannabinoids present in female Cannabis
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Other plants contain phytocannabinoids that bind CB2 receptor and/or modulate
endocannabinoids – e.g Echinecea
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931553/pdf/bph0160‐0523.pdf
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Cannabis
At least 483 compounds identified to‐date in Cannabis, >60 are cannabinoids
Cannabis sativa, Cannabis indica, Cannabis ruderalis
Cannabinoids and Terpenoids Secreted by Glandular Trichomes
Trichomes most abundant on the female flowers
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Cannabinoid Receptors
CB1 and CB2 subtypes identified to‐date; potentially additional receptors exist Involved in appetite, mood, pain sensation and memory
Present on cells in brain that repress neurotransmitter release, as well as peripheral cells
Cannabinoid Receptors
CB1 – Identified in 1988
Present primarily in brain – basal ganglia, limbic system, hippocampus, cerebellum
Absent in region of brain stem responsible for respiration and cardiovascular functioning
Fatal doses of THC est. 20,000 – 40,000 typically ingested doses
CB2 – Identified in early 1990s
CB2 Identified in early 1990s
Expressed on T cells, B cells, macrophages, hematopoetic cells as well as peripheral nerve terminals
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Cannabinoid Receptors
CB1
Euphoric and anticonvulsant effects attributed to activation of CB1 receptor
CB2
Anti‐inflammatory, other potential therapeutic effects attributed to activation of CB2 receptor
THC, CBD and CBN – Most Extensively Studied Phytocannabinoids
Tetrahydrocannabinol (THC)
Cannabidiol (CBD)
Cannabinol ((CBN))
Concentration ranges from 1 ‐ 40% of plant extract
Up to 40% of plant extract
(variable)
Trace amounts though increases over time (THC degradation product)
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Tetrahydrocannabinol (THC)
• Structure determined in 1964
• Agonist of CB
Agonist of CB1 and CB
and CB2 receptors
• Primary psychoactive component in Cannabis
Subjective effects of THC affected by other cannabinoids
Cannabidiol (CBD)
• Structure determined in 1940s
Does not have psychoactive properties on its own though antagonizes some effects of THC
• Does not have psychoactive properties on its own though antagonizes some effects of THC
‐ antipsychotic ‐ anxiolytic
• CB2 inverse agonist, 5‐HT1A agonist, antagonist of putative new CB receptor GRP55
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Cannabinol (CBN)
• Structure determined in early 1940s
• Weakly psychoactive
Weakly psychoactive
• Higher affinity for CB2 receptors
• Degradation product of THC oxidation – concentration increases over time
and with exposure to light and air
Tetrahydrocannabinolic acid (THCA) – Plant Precursor to THC
THCA
Non‐psychoactive
THC
Psychoactive
“THC” present in Cannabis exists mostly as THCA – assumed self‐defense role for plant
Drying or heating the plant material (smoking or vaporizing) converts THCA to THC
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THC Chemical Properties
• Glassy solid / sticky solid depending on temperature
• Low water solubility
Low water solubility
• Soluble in organic solvents – can be extracted by various methods
• Boiling point 250 °C THC Pharmacokinetics
Absorption
Smoked/vaporized, oral, transdermal, sublingual, rectal suppository
Effects last 2 3 hours or less if smoked longer if taken orally
Effects last 2‐3 hours or less if smoked –
longer if taken orally
Smoking/vaporizing allows titration of desired dose
Distribution
Accumulates in lipophilic tissues
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THC Pharmacokinetics
Metabolism
Primarily occurs in liver – lesser extent in intestines, brain, heart, lung, other tissues
Primarily occurs in liver lesser extent in intestines, brain, heart, lung, other tissues
>100 metabolites formed
Primary route – oxidative metabolism followed by conjugation to more water‐soluble metabolite
THC Metabolism – Primary Route
OH
H
OH
H
O
THC
HO
11‐OH‐THC
Psychoactive metabolite
O
H
OH
Biphasic effects may be attributed to active metabolites.
11‐OH‐THC potentially causes increased appetite.
H
O
THC‐COOH
Inactive metabolite
Drug screens analyze inactive metabolite THC‐COOH
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Excretion of THC and Its Metabolites
HO
O
H
OH
H
O
THC COOH glucuronide
THC‐COOH‐glucuronide
THC COOH
THC‐COOH
Predominately THC‐COOH and THC‐COOH‐glucuronide excreted in urine.
Trace THC excreted in urine, and some 11‐OH‐THC excreted in feces.
Synthetic Cannabinoids
FDA approved for:
1. Chemotherapy induced nausea
Dronabinol (Marinol®)
2. AIDS‐related anorexia
Synthetic THC (sesame oil formulation)
Schedule III
Oral dosing effects after ca. 1 h (versus smoking – seconds‐minutes)
More acute psychedelic effects than Cannabis which contains other cannabinoids
Fixed dose versus titrate‐able dose when smoking 9
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Synthetic Cannabinoids
O
H
OH
FDA approved for:
H
O
1. Chemotherapy induced nausea
(antiemetic)
Nabilone (Cesamet®)
2. Analgesic for neuropathic pain
Synthetic THC analog
Synthetic THC analog
Schedule II
Combination of THC and CBD Containing Plant Isolates
Nabiximols (Sativex®)
Standardized composition, formulation, and doses of THC (2.7 mg) and CBD (2.5 mg)
Compounds derived from Cannabis plant
Nabiximols currently in Phase III clinical trials in US
Approved for multiple sclerosis in Canada, New Zealand, UK, and several European countries
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