THC
Brandon Connor
UW-Eau Claire
Indian Medicine
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Treatment of cramps
Migraine
Convulsions
Neuralgia
Attenuation of nausea and vomiting
Decreased intestinal motility during diarrhea
Bronchodialation in asthma
Appetite stimulation
Isolation of THC
Y. Gaoni and R. Mechoulan completed
work by R. Adams in 1940’s.
 Belongs to cannabinoid family
 Geranyl-pyrophosphate and olivetol
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Vincenzo Di Marzo
THC
1,1’-di-methyl-pyrane ring (B ring)
Variedly derivatized aromatic ring (C ring)
Variedly unsaturated cyclohexyl ring (A ring)
OH
O
Further Pharmacological
Properties
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1986-300 analogs and related compounds were
available
Analgesic
Anti-emetic
Anti-inflammatory
Bronchodilatory
Anti-convulsant
Reduction of ocular blood pressure
Alleviation of neurological disorders
Continued
Multiple sclerosis, Huntington’s chorea,
spinal cord injury associated spasticity and
seizures.
 Abortive and anti-fertiltiy actions
 Various metabolic effects
 Modulation of prostaglandins or pituitary
and steroid hormones
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Structure-Activity
Relationship (SAR)
Tetrad of behavioral tests on mice (Martin)
 1) Antinociception-tail flick latency
 2) Catalepsy-ring stand test
 3) Rectal temperature
 4) Spontaneous activity in open field test
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Results of SAR
Psychoactive properties are (-) transenatioselective
 Length, lipophilicity C3 alkyl chain
 Phenolic hydroxyl-group
 C9 substitute
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OH
O
Discovery of Cannabinoid
Receptor
Cp-55,940 4-25 times more potent
 Amino-alkylindoles (WIN 55,212-2)
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O
OH
N
HO
N
O
Cloning of Receptor
1990-Matsuda clones receptor using
“homology screening” approach
 Oligonucleotide probe
 “Orphan receptor”
 Concomitantly Gerard et. al. reports human
receptor
 98% homology to rat receptor
 Expressed in Testes
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SN Substantia Nigra -- the cannabinoid binding is highest here
GP Globus Pallidus -- second-highest region of binding
Caud Caudate Nucleus -- believed to control repetitive movement
Pu Putamen
Hip Hippocampus -- where short term memory is processed into long term
memory
Am Amygdala -- the part of the brain controlling rage, lust, fear and other
strong emotions
Hy Hypothalmus -- where vital endocrine hormones are released
Central Receptors
Seven trans-membrane spanning receptor
family
 1) Seven alpha-helices
 2) Three extra- and intra-celluar loops
 3) Glycosylated extra-celluar N-terminal
domain
 4) Intra-celluar C-terminal domain
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Continued
32-39% homolgy to adrenocorticotropic
hormone and melanocortin receptors
 Lack of disulfide bond between 1st and 2nd
extracelluar loop
 Lack of proline residue between 4th and 5th
trans-membrane domain
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Steve Alexander
Peripheral Receptor
Three years later a peripheral receptor is
cloned
 44% identity with central receptor
 68% identity within helical regions
 CB1 and CB2
 Not present in thymus, liver, lung, kidneys
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Steve Alexander
Important Findings
Distribution correlated well with
pharmacological actions
 Agonists which selectively bind to CB2
 Antagonists which do not activate G-protein
 SR141716A- CB1 antagonist
 THC- weak antagonist at CB2
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Intracelluar effects of THC
Inhibition of agonist-induced cAMP
formation
 Inhibition of N-type Ca channels
 Interference with gamma-aminobutyric
acid, acetylcholine, and the catecholamines
 Pertussis toxin
 ADP-ribosylation and subsequent
inactivation
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Vincenzo Di Marzo
Discovery of Endocannabinoids
Lipophilic molecule like THC
 1992-Devane isolated brain constituent
 NMR GC/MS analysis
 Derivative of arachidonic (prostaglandins,
thromboxanes, leukotrienes, etc.)
 Presence of amidated ethanolamine
 Cis-5,8,11,14-eicosatetraenoyl-N-(2hydroxy-ethyl)-amine
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Continued
Anandamide- Sanskrit for “bliss”, ananda
 Shared most of the pharmacological
properties with THC
 Located where receptors are present
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O
OH
N
Physiological Roles
Role of cannabinoid system remains elusive
 Widespread tuning system of finely tuned
tasks
 Modulation of neurotransmitter
release/action at autonomic and sensory
fibers
 Control of immunological, gastrointestinal,
reproductive, cardiovascular performance
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Continued
Thermoregulatory centers
 Regulation of perceptive, cognitive, motor
functions
 Suggested roles in synaptic plasticity, brain
development
 Hypothalmic hormone secretion
 Release of dynorphins-analgesic
 Lowers blood pressure and heart rate
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Immune system
Autoimmune encephalomyelitis
 Placebo-95% died; THC-98% lived
 Antigen-specific effect on macrophages
 Mitogen-activated protein kinase
 Suppression of immune system and
tumoicidial cells
 Protection of nerve cells from exitotoxins
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Reproductive System
Control of spermatogenesis and male
fertility
 Receptors found in sea urchin eggs
 May be used to direct timing and placing of
embryo implantation
 Suggested to mediate communication
between uterus and embryo.
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References
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nepenthes.lycaeum.org/Drugs/THC/index.html
www.nott.ac.uk/physpharm/cannabinoid.html
www.druglibrary.org/schaffer/hemp/BRAIN.htm
bctv.butte.cc.ca.us/ads/Marijuana%20Chapter/sld0
01.htm
www.umds.ac.uk/neupharm/can.htm
www.lacbc.org
Www.netscijournal.com/97v1/97007/cabb.htm#Introduction