1. THC Brandon Connor UW-Eau Claire

2. Indian Medicine n Treatment of cramps n Migraine n Convulsions n Neuralgia n Attenuation of nausea and vomiting n Decreased intestinal motility during diarrhea n Bronchodialation in asthma n Appetite stimulation

3. Isolation of THC n Y. Gaoni and R. Mechoulan completed work by R. Adams in 1940’s. n Belongs to cannabinoid family n Geranyl-pyrophosphate and olivetol

4. Vincenzo Di Marzo

5. THC 1,1’-di-methyl-pyrane ring (B ring) Variedly unsaturated cyclohexyl ring (A ring) Variedly derivatized aromatic ring (C ring)

6. Further Pharmacological Properties n 1986-300 analogs and related compounds were available n Analgesic n Anti-emetic n Anti-inflammatory n Bronchodilatory n Anti-convulsant n Reduction of ocular blood pressure n Alleviation of neurological disorders

7. Continued n Multiple sclerosis, Huntington’s chorea, spinal cord injury associated spasticity and seizures. n Abortive and anti-fertiltiy actions n Various metabolic effects n Modulation of prostaglandins or pituitary and steroid hormones

8. Structure-Activity Relationship (SAR) n Tetrad of behavioral tests on mice (Martin) n 1) Antinociception-tail flick latency n 2) Catalepsy-ring stand test n 3) Rectal temperature n 4) Spontaneous activity in open field test

9. Results of SAR n Psychoactive properties are (-) trans- enatioselective n Length, lipophilicity C 3 alkyl chain n Phenolic hydroxyl-group n C 9 substitute

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

11. Cloning of Receptor n 1990-Matsuda clones receptor using “homology screening” approach n Oligonucleotide probe n “Orphan receptor” n Concomitantly Gerard et. al. reports human receptor n 98% homology to rat receptor n 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 n Seven trans-membrane spanning receptor family n 1) Seven alpha-helices n 2) Three extra- and intra-celluar loops n 3) Glycosylated extra-celluar N-terminal domain n 4) Intra-celluar C-terminal domain

14. Continued n 32-39% homolgy to adrenocorticotropic hormone and melanocortin receptors n Lack of disulfide bond between 1st and 2nd extracelluar loop n Lack of proline residue between 4th and 5th trans-membrane domain

15. Steve Alexander

16. Peripheral Receptor n Three years later a peripheral receptor is cloned n 44% identity with central receptor n 68% identity within helical regions n CB1 and CB2 n Not present in thymus, liver, lung, kidneys

17. Steve Alexander

18. Important Findings n Distribution correlated well with pharmacological actions n Agonists which selectively bind to CB2 n Antagonists which do not activate G-protein n SR141716A- CB1 antagonist n THC- weak antagonist at CB2

19. Intracelluar effects of THC n Inhibition of agonist-induced cAMP formation n Inhibition of N-type Ca channels n Interference with gamma-aminobutyric acid, acetylcholine, and the catecholamines n Pertussis toxin n ADP-ribosylation and subsequent inactivation

20. Vincenzo Di Marzo

21. Discovery of Endocannabinoids n Lipophilic molecule like THC n 1992-Devane isolated brain constituent n NMR GC/MS analysis n Derivative of arachidonic (prostaglandins, thromboxanes, leukotrienes, etc.) n Presence of amidated ethanolamine n Cis-5,8,11,14-eicosatetraenoyl-N-(2- hydroxy-ethyl)-amine

22. Continued n Anandamide- Sanskrit for “bliss”, ananda n Shared most of the pharmacological properties with THC n Located where receptors are present

23. Physiological Roles n Role of cannabinoid system remains elusive n Widespread tuning system of finely tuned tasks n Modulation of neurotransmitter release/action at autonomic and sensory fibers n Control of immunological, gastrointestinal, reproductive, cardiovascular performance

24. Continued n Thermoregulatory centers n Regulation of perceptive, cognitive, motor functions n Suggested roles in synaptic plasticity, brain development n Hypothalmic hormone secretion n Release of dynorphins-analgesic n Lowers blood pressure and heart rate

25. Immune system n Autoimmune encephalomyelitis n Placebo-95% died; THC-98% lived n Antigen-specific effect on macrophages n Mitogen-activated protein kinase n Suppression of immune system and tumoicidial cells n Protection of nerve cells from exitotoxins

26. Reproductive System n Control of spermatogenesis and male fertility n Receptors found in sea urchin eggs n May be used to direct timing and placing of embryo implantation n Suggested to mediate communication between uterus and embryo.

27. References n nepenthes.lycaeum.org/Drugs/THC/index.html n www.nott.ac.uk/physpharm/cannabinoid.html n www.druglibrary.org/schaffer/hemp/BRAIN.htm n bctv.butte.cc.ca.us/ads/Marijuana%20Chapter/sld0 01.htm n www.umds.ac.uk/neupharm/can.htm n www.lacbc.org n Www.netsci- journal.com/97v1/97007/cabb.htm#Introduction