THC

Brandon Connor

UW-Eau Claire

Indian Medicine

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

Vincenzo Di Marzo

THC

O

O

H

1,1’-di-methyl-pyrane ring (B ring)

Variedly unsaturated cyclohexyl ring (A ring)Variedly derivatized aromatic ring (C ring)

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

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

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

Results of SAR

Psychoactive properties are (-) trans-enatioselective

Length, lipophilicity C3 alkyl chain

Phenolic hydroxyl-group C9 substitute

O

O

H

Discovery of Cannabinoid Receptor Cp-55,940 4-25 times more potent Amino-alkylindoles (WIN 55,212-2)

O

H

O

H

N

N

O

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

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

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

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

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

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

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-(2-hydroxy-

ethyl)-amine

Continued

Anandamide- Sanskrit for “bliss”, ananda Shared most of the pharmacological

properties with THC Located where receptors are present

O

H

N

O

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

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

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

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.

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/Marijuana%20Chapter/

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

cabb.htm#Introduction