Spekter delovanja kanabinoidov
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1 Janez Konc Spekter delovanja kanabinoidov Učno gradivo za študente univerzitetnega študijskega programa 2. stopnje Biopsihologija pri predmetu Psihofarmakologija duševnih motenj Univerza na Primorskem, Fakulteta za matematiko, naravoslovje in informacijske tehnologije Glagoljaška 8, SI-6000, Koper, Slovenija Koper, 2015
2 Spekter delovanja kanabinoidov; Učno gradivo pri predmetu Psihofarmakologija duševnih motenj Namenjeno študentom univerzitetnega študijskega programa 2.stopnje Biopsihologija, Univerza na Primorskem, Glagoljaška 8, SI-6000, Koper, Slovenija Avtor: Janez Konc Izšlo: Koper, 2015
3 Endokanabinoidni sistem skupina endogenih kanabionidnih receptorjih v možganih in perfiernem živčevju uravnavajo: apetit, občutek bolečine, voljo, spomin, psihoaktivni efekti CB1 (in CB2 tip endogeni ligand za CB1 tip receptorjev je endokanabinoid anandamide in 2-arachidonoylglycerol sicer najbolj znani THC tetrahydrocannabinol (THC) anandamide
4 Endokanabinoidni sistem Sistem sestavljajo: endogeni kanabinoidi anandamide in 2-arachidonoylglycerol encimi, ki sintetizirajo in razgrajujejo endokanabinoide, npr. FAAH - fatty acid amide hydrolase in monoacylglycerol lipase kanabinoidni receptorji (tipa: CB1 in CB2) z G-proteini sklopljeni receptorji obstajajo tudi drugi receptorji za kanabinoide, a še ne dovolj raziskani
5 Sinteza, sproščanje in razgradnja Sinteza: impulz zvišanje intracelularnega Ca2+ transacylase (katalizira 1. korak sinteze) anandamide ali 2-AG Sproščanje: endokanabinoidni transporter ekstracelularni prostor receptorji celica glije Razgradnja: fatty acid amide hydrolase (FAAH) arahidonska kislina + etanolamin
6 Delovanje Aktivacija CB1 receptorjev: Znižanje koncentracije camp zaradi inhibicije adenilil ciklaze Aktivacija MAP kinaz Povečana ekspresija myelin basic proteina, endoplasmatskih proteinov, citohrom oksidaze Zmanjšana ekspresija calmodulina in ribosomske RNA Aktivacija transkripcijskih faktorjev
7 Delovanje Spomin: Miške, ki so jim dajali tetrahidrokanabinol (THC), imajo slabši dolgoročni spomin. (zaradi vpliva THC na hipokampus) Miške brez CB1 receptorjev imajo boljši dolgoročni spomin CB1 vplivajo na pozabljanje Apetit: CB1 receptorji naj bi imeli v hipotalamusu vpliv na tek Več CB1 debelost Inverzni agonist CB1 (rimonabant) hujšanje hipotalamus Metabolizem: Modulira senzitivnost na inzulin Stres zmanjšuje stres (prilagodi izločanje glukokortikoidov ob daljšem stresu)
8 Delovanje II Imunska funkcija: Imunomodulatorji Multipla skleroza: blažijo mišične krče Reprodukcija Reprodukcija: Vpliv na usidranje zarodka (odvisen od koncentracije agonista) Analgezija: Palmitoylethanolamide: učinkovito blaži bolečino Termoregulacija: Agonistično delovanje na TRPV1 kanale Spanje: Pozitiven vpliv na spanje
9 Delovanje II Imunska funkcija: Imunomodulatorji Multipla skleroza: blažijo mišične krče Reprodukcija Reprodukcija: Vpliv na usidranje zarodka (odvisen od koncentracije agonista) Analgezija: Palmitoylethanolamide: učinkovito blaži bolečino Termoregulacija: Agonistično delovanje na TRPV1 kanale Spanje: Pozitiven vpliv na spanje
10 Kanabinoidi endogeni: anandamide... fitokanabinoidi: THC sintezni kanabinoidi: klasični (podobni THC), neklasični (aminoalkilindoli, 1,5-diarilpirazoli, kinoloni, arulsulfonamidi...)
11 Fitokanabinoidi
12 Fitokanabinoidi Cannabis Najdemo jih tudi v ameriškem slamniku (družina Echinacea) CB2 receptorji vpliv na imunski sistem
13 Farmakologija večina vnešenega THC se metabolizira v jetrih (citohrom P450) inhibitorji citohromov močnejši učinek kopičenje v maščobi
14 Endokanabinoidi anandamid (odkrit 1992) 2-arahidonoilglicerol Zaradi hidrofobnosti so sintetizirani po potrebi (ne shranjujejo se v veziklih). Iz istega razloga ne potujejo daleč od izvora.
15 Sintezni kanabinoidi Dronabinol povečuje apetit Nabilone enako Rimonabant (inverzni agonist) proti debelosti Drugi mehanizmi: inhibitorji FAAH (zvišujejo koncentracijo endokanabinoidov) HU-331 (inhibitor DNA topoizomeraze) proti raku HU-331
16 Enhancerji endokanabinoidov inhibitorji fatty acid amide hydrolase (FAAH) katabolizira endokanabinoidi inhibitor FAAH zvišana koncentracija endokanabinoidov problem FAAH: obstaja >200 podobnih proteinov možni off-target efekti Podobni proteini s ProBiSom: FAAH (PDB ID: 3PPM)
17 Inhibitorji in aktivatorji FAAH JNJ : pri anksioznosti, kovalentni inhibitor BIA : anksioznosti, Parkinson LY : analgezija, anksioznost, slaba selektivnost
18 ProBiS vezavna mesta na FAAH Dve vezavni mesti z dvema ko-kristaliziranima inhibitorjema na FAAH
19 Antagonisti na kanabinoidnih receptorjih antagonisti inverzni agonisti protitelesa za CB receptorje Antagonisti: Sintezni: rimonabant: proti debelosti Naravni: kanabidiol CB1 protitelesa: V Rusiji sta registrirani dve: brizantin (za odvajanje od kajenja) distressa (za hujšanje) rimonabant
20 Zaviralci reputake endokanabinoidov analgezija povečan apetit izboljšanje volje inhibicija kratkoročnega spomina zmanjševanje tumorjev (nepojasnjeno) VDM-11
21 Zdravljenje slabosti Kanabinoidi : so koristen dodatek k sodobni antiemetični terapiji pri izbranih bolnikih. Kažejo kombinacijo učinkovitosti proti bruhanju s potencialno koristnimi stranskimi učinki, kot so sedacija in evforija. Vendar pa je njihova uporaba praviloma omejena z visoko incidenco toksičnih učinkov, kot so omotica, disforija, in halucinacije. Nekatere študije so pokazale, da so kanabinoidi nekoliko boljši od običajnih antiemetikov kot metoklopramid, fenotiazini in haloperidol pri preprečevanju slabosti in bruhanja. Kanabinoidi so opcija pri ljudeh, ki ne prenašajo ali so neodzivni na 5 - HT3 ali steroide.
22 Uporaba sintetičnih kanabinoidov sintezni kanabinoidi so popularni med mladimi uživalci akutna toksičnost dolgotrajno uživanje vodi v odvisnost
23 Uporaba sintetičnih kanabinoidov
24 Uporaba sintetičnih kanabinoidov
25 Uporaba sintetičnih kanabinoidov Delta-9-THC in sintezni kanabinoidi
26 Terapije omogočene s CB2 agonisti
27 Singerstični učinki CB agonistov z drugimi učinkovinami
28 Singerstični učinki CB agonistov z drugimi učinkovinami
29 Lipoksin-A4 je alosterični agonist na CB1 receptorjih lipoxin A4 Izboljša afiniteto anandamida do receptorja CB1, s čimer se poveča učinek tega endokanabinoida.
30 Nevroprotektivno delovanje CB1 receptorjev Kanabinoidi in endokanabinoidi spodbujajo nevroprotektivno delovanje pri laboratorijskih živalih z aktivacijo CB1 kanabinoidnih receptorjev na glutamatergičnih sinapsah.
31 Zaščita pred pljučno fibrozo po radiaciji Sevanje povzročo pljučno fibrozo in je hud zaplet pri radioterapiji prsnega koša, ki omejuje njegovo odmerjanje, intenzivnost in trajanje. Nedavno so ugotovili, da CB1 signalizacija igra ključno vlogo pri patološkem razvoju z radiacijo povzročenega pljučnega vnetja in fibroze. Periferno omejeni CB1 antagonisti lahko predstavljajo nov terapevtski pristop proti temu uničujočemu zapletu radioterapije.
32 Vloga endokanabinoidov v pre-frontalni limbični poti na spomin Ugotovili so, da endokanabinoidi spodbujajo spomin na čustveno intenzivne dogodke.
33 Funkcija FAAH Računalniško modeliranje strukture FAAH in dveh endogenih kanabinoidov.
34 Funkcija FAAH FAAH katalitični cikel Superpozicija dveh vezavnih mest FAAH.
35 Tetrahidro-b-karbolini inhibitorji FAAH
36 Tetrahidro-b-karbolini inhibitorji FAAH Sinteza derivatov
37 Tetrahidro-b-karbolini inhibitorji FAAH Aktivnost na FAAH, TRPV in TRPA.
38 Zaščita pred anksioznostjo in stresom Vloga FAAH pri patofiziologiji in zaščiti pred stresom.
39 Zaščita pred anksioznostjo in stresom
40 FAAH in placebo efekt FAAH Pro129/Pro129 homozygotes, who constitute nearly half of the population, reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration; no effects on pain report in the absence of placebo were observed.
41 Ideje za seminarje
42 Viri in literatura 1. Bronova, I., Smith, B., Aydogan, B., Weichselbaum, R.R., Vemuri, K., Erdelyi, K., Makriyannis, A., Pacher, P. and Berdyshev, E., Peripheral Targeting of CB1 Cannabinoid Receptors Protects from Radiation-Induced Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology. 2. Pecina, M., Martínez-Jauand, M., Hodgkinson, C., Stohler, C.S., Goldman, D. and Zubieta, J.K., FAAH selectively influences placebo effects. Molecular psychiatry, 19(3), pp Palermo, G., Rothlisberger, U., Cavalli, A. and De Vivo, M., Computational insights into function and inhibition of fatty acid amide hydrolase. European journal of medicinal chemistry, 91, pp Harris, C.R. and Brown, A., Synthetic cannabinoid intoxication: a case series and review. The Journal of emergency medicine, 44(2), pp Pertwee, R.G., Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philosophical Transactions of the Royal Society B: Biological Sciences, 367(1607), pp Pamplona, F.A., Ferreira, J., de Lima, O.M., Duarte, F.S., Bento, A.F., Forner, S., Villarinho, J.G., Bellocchio, L., Wotjak, C.T., Lerner, R. and Monory, K., Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proceedings of the National Academy of Sciences, 109(51), pp Chiarlone, A., Bellocchio, L., Blázquez, C., Resel, E., Soria-Gómez, E., Cannich, A., Ferrero, J.J., Sagredo, O., Benito, C., Romero, J. and Sánchez-Prieto, J., A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proceedings of the National Academy of Sciences, 111(22), pp Morena, M., Roozendaal, B., Trezza, V., Ratano, P., Peloso, A., Hauer, D., Atsak, P., Trabace, L., Cuomo, V., McGaugh, J.L. and Schelling, G., Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training. Proceedings of the National Academy of Sciences, 111(51), pp Booker, L., Kinsey, S.G., Abdullah, R.A., Blankman, J.L., Long, J.Z., Ezzili, C., Boger, D.L., Cravatt, B.F. and Lichtman, A.H., The fatty acid amide hydrolase (FAAH) inhibitor PF 3845 acts in the nervous system to reverse LPS induced tactile allodynia in mice. British journal of pharmacology, 165(8), pp Ortar, G., De Petrocellis, L., Moriello, A.S., Allarà, M., Morera, E., Nalli, M. and Di Marzo, V., Tetrahydro-β-carboline derivatives targeting fatty acid amide hydrolase (FAAH) and transient receptor potential (TRP) channels. Bioorganic & medicinal chemistry letters, 23(1), pp Gunduz-Cinar, O., Hill, M.N., McEwen, B.S. and Holmes, A., Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends in pharmacological sciences, 34(11), pp Wikipedija
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