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THC

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.

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THC

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  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 1940’s. • 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, 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

  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/Marijuana%20Chapter/sld001.htm • www.umds.ac.uk/neupharm/can.htm • www.lacbc.org • Www.netsci-journal.com/97v1/97007/cabb.htm#Introduction

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