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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
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
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
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
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.