THC

1
THC

• Brandon Connor
• UW-Eau Claire

2
Indian Medicine

• Treatment of cramps
• Migraine
• Convulsions
• Neuralgia
• Attenuation of nausea and vomiting
• Decreased intestinal motility during diarrhea
• Bronchodialation in asthma
• Appetite stimulation

3
Isolation of THC

• Y. Gaoni and R. Mechoulan completed work by R.
  Adams in 1940s.
• Belongs to cannabinoid family
• Geranyl-pyrophosphate and olivetol

4
Vincenzo Di Marzo
5
THC
1,1-di-methyl-pyrane ring (B ring)
Variedly derivatized aromatic ring (C ring)
Variedly unsaturated cyclohexyl ring (A ring)
6
Further Pharmacological Properties

• 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

7
Continued

• Multiple sclerosis, Huntingtons chorea, spinal
  cord injury associated spasticity and seizures.
• Abortive and anti-fertiltiy actions
• Various metabolic effects
• Modulation of prostaglandins or pituitary and
  steroid hormones

8
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

9
Results of SAR

• Psychoactive properties are (-)
  trans-enatioselective
• Length, lipophilicity C3 alkyl chain
• Phenolic hydroxyl-group
• C9 substitute

10
Discovery of Cannabinoid Receptor

• Cp-55,940 4-25 times more potent
• Amino-alkylindoles (WIN 55,212-2)

11
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

12

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
13
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

14
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

15

Steve Alexander
16
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

17
Steve Alexander
18
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

19
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

20
Vincenzo Di Marzo
21
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-(2-hydroxy-ethyl)
  -amine

22
Continued

• Anandamide- Sanskrit for bliss, ananda
• Shared most of the pharmacological properties
  with THC
• Located where receptors are present

23
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

24
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

25
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

26
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.

27
References

• 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/Marijuana20Chapter/sld001
  .htm
• www.umds.ac.uk/neupharm/can.htm
• www.lacbc.org
• Www.netsci-journal.com/97v1/97007/cabb.htmIntrodu
  ction