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THCIndian MedicineIsolation of THCSlide 4Slide 5Further Pharmacological PropertiesContinuedStructure-Activity Relationship (SAR)Results of SARDiscovery of Cannabinoid ReceptorCloning of ReceptorCentral ReceptorsSlide 14Peripheral ReceptorSlide 17Important FindingsIntracelluar effects of THCSlide 20Discovery of EndocannabinoidsSlide 22Physiological RolesSlide 24Immune systemReproductive SystemReferencesTHCBrandon ConnorUW-Eau ClaireIndian MedicineTreatment of crampsMigraineConvulsionsNeuralgiaAttenuation of nausea and vomitingDecreased intestinal motility during diarrheaBronchodialation in asthmaAppetite stimulationIsolation of THCY. Gaoni and R. Mechoulan completed work by R. Adams in 1940’s.Belongs to cannabinoid familyGeranyl-pyrophosphate and olivetolVincenzo Di MarzoTHC 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 disordersContinued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 hormonesStructure-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 testResults of SARPsychoactive properties are (-) trans-enatioselectiveLength, lipophilicity C3 alkyl chainPhenolic hydroxyl-groupC9 substitute O O HDiscovery of Cannabinoid ReceptorCp-55,940 4-25 times more potentAmino-alkylindoles (WIN 55,212-2) O H O H N N O OCloning 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 TestesSN 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 releasedCentral 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 domainContinued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 domainSteve AlexanderPeripheral 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, kidneysSteve AlexanderImportant 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 CB2Intracelluar 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 inactivationVincenzo Di MarzoDiscovery 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)-amineContinuedAnandamide- Sanskrit for “bliss”, anandaShared most of the pharmacological properties with THCLocated where receptors are present O H N OPhysiological 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 performanceContinued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 rateImmune 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 exitotoxinsReproductive 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


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UWEC CHEM 412 - THC

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