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 MedicineTreatment of crampsMigraineConvulsionsNeuralgiaAttenuation of nausea and vomitingDecreased intestinal motility during diarrheaBronchodialation in asthmaAppetite stimulationIsolation of THCY. Gaoni and R. Mechoulan completed work by R. Adams in 1940’s.Belongs to cannabinoid familyGeranyl-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 Properties1986-300 analogs and related compounds were availableAnalgesicAnti-emeticAnti-inflammatoryBronchodilatoryAnti-convulsantReduction of ocular blood pressureAlleviation of neurological disordersContinuedMultiple sclerosis, Huntington’s chorea, spinal cord injury associated spasticity and seizures.Abortive and anti-fertiltiy actionsVarious metabolic effectsModulation of prostaglandins or pituitary and steroid hormonesStructure-Activity Relationship (SAR)Tetrad of behavioral tests on mice (Martin)1) Antinociception-tail flick latency2) Catalepsy-ring stand test3) Rectal temperature4) Spontaneous activity in open field testResults of SARPsychoactive properties are (-) trans-enatioselectiveLength, lipophilicity C3 alkyl chainPhenolic hydroxyl-groupC9 substitute O O HDiscovery of Cannabinoid ReceptorCp-55,940 4-25 times more potentAmino-alkylindoles (WIN 55,212-2) O H O H N N O OCloning of Receptor1990-Matsuda clones receptor using “homology screening” approachOligonucleotide probe“Orphan receptor”Concomitantly Gerard et. al. reports human receptor98% homology to rat receptorExpressed 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 ReceptorsSeven trans-membrane spanning receptor family1) Seven alpha-helices2) Three extra- and intra-celluar loops3) Glycosylated extra-celluar N-terminal domain4) Intra-celluar C-terminal domainContinued32-39% homolgy to adrenocorticotropic hormone and melanocortin receptorsLack of disulfide bond between 1st and 2nd extracelluar loopLack of proline residue between 4th and 5th trans-membrane domainSteve AlexanderPeripheral ReceptorThree years later a peripheral receptor is cloned44% identity with central receptor68% identity within helical regionsCB1 and CB2Not present in thymus, liver, lung, kidneysSteve AlexanderImportant FindingsDistribution correlated well with pharmacological actionsAgonists which selectively bind to CB2Antagonists which do not activate G-proteinSR141716A- CB1 antagonistTHC- weak antagonist at CB2Intracelluar effects of THCInhibition of agonist-induced cAMP formationInhibition of N-type Ca channelsInterference with gamma-aminobutyric acid, acetylcholine, and the catecholaminesPertussis toxinADP-ribosylation and subsequent inactivationVincenzo Di MarzoDiscovery of EndocannabinoidsLipophilic molecule like THC1992-Devane isolated brain constituentNMR GC/MS analysisDerivative of arachidonic (prostaglandins, thromboxanes, leukotrienes, etc.)Presence of amidated ethanolamineCis-5,8,11,14-eicosatetraenoyl-N-(2-hydroxy-ethyl)-amineContinuedAnandamide- Sanskrit for “bliss”, anandaShared most of the pharmacological properties with THCLocated where receptors are present O H N OPhysiological RolesRole of cannabinoid system remains elusiveWidespread tuning system of finely tuned tasksModulation of neurotransmitter release/action at autonomic and sensory fibersControl of immunological, gastrointestinal, reproductive, cardiovascular performanceContinuedThermoregulatory centersRegulation of perceptive, cognitive, motor functionsSuggested roles in synaptic plasticity, brain developmentHypothalmic hormone secretionRelease of dynorphins-analgesicLowers blood pressure and heart rateImmune systemAutoimmune encephalomyelitisPlacebo-95% died; THC-98% livedAntigen-specific effect on macrophagesMitogen-activated protein kinaseSuppression of immune system and tumoicidial cellsProtection of nerve cells from exitotoxinsReproductive SystemControl of spermatogenesis and male fertilityReceptors found in sea urchin eggsMay be used to direct timing and placing of embryo implantationSuggested to mediate communication between uterus and embryo.Referencesnepenthes.lycaeum.org/Drugs/THC/index.htmlwww.nott.ac.uk/physpharm/cannabinoid.htmlwww.druglibrary.org/schaffer/hemp/BRAIN.htmbctv.butte.cc.ca.us/ads/Marijuana%20Chapter/sld001.htmwww.umds.ac.uk/neupharm/can.htmwww.lacbc.org
View Full Document