Opredelitev farmakoloških receptorjev
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1 Univerzitetni podiplomski študij Biomedicina Modul 1: Farmakološke metode Opredelitev farmakoloških receptorjev Mojca Kržan Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
2 Mesta delovanja zdravil
3 Mesta delovanja zdravil proteini Encimi Transporterji Hormoni, vitamini DNA-protein RNA-protein Farmakološki receptorji (ionski kanali, s proteini-g sklopljeni)
4 John Newport Langley in Paul Erlich 1904 je T. Elliott predlagal, da obstaja biokemična povezava med živčnim končičem in tarčnim organom je J.N. Langley opisal receptivno substanco kot mesto, kjer učinkuje nevrotransmitor Približno hkrati je P. Erlich predlagal, da se na receptorje vežejo toksini in hrana; 1907 pa je predlagal, da je za učinkovanje zdravil nujna vezava na chemoceptor
5 Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v
6
7 Farmakološki laboratorij okoli leta 1910
8 Odnos med koncentracijo in učinkom Ariens, Furchgott, Clark, Stephenson in Schild so premaknili koncept receptorjev iz teorije v enačbe. E E p 50 ECm A A p p
9 Guide to Receptors and Channels SPH Alexander, A Mathie, JA Peters British J Pharmacol Volume 150, Issue S1 (February 2007)
10 Opredelitev receptorja Ime receptorja Druga imena - sinonimi Endogeni agonist (?) Identifikacijska številka v Ensembl ID bazi Glavni transdukcijski signal Velikostni red afinetet/moči posameznih ligandov Selekivni agonisti Selektivni antagonisti Radioaktivni ligandi Gen (?)
11 Kaj lahko opredelimo z vezavni študijami Ime receptorja Druga imena - sinonimi Identifikacijska številka v Ensembl ID bazi Glavni transdukcijski signal Velikostni red afinetet/moči posameznih ligandov Selekivni agonisti Selektivni antagonisti Radioaktivni ligandi
12 Osnovni koraki vezavne študije
13 Potek poskusa Potrebujemo: tkivo, ki vsebuje receptor radioligand primerno okolje (temperatura, ph )
14 Inkubacija Radioligand in tkivo inkubiramo določen čas, da omogočimo potek reakcije
15 Vzpostavi se ravnotežje med vezanim in nevezanim radioligandom Ravnotežje
16 Separacija Ločimo vezan od nevezanega radioliganda centrifugiranje, filtracija, dializa
17 Detekcija Izkoriščamo radioaktivni razpad izotopa Merimo število razpadov na minuto Dpm desintegrations per minute Cpm counts per minute
18 Primer merjenja cpm in dpm vrednosti v scintilacijskem števcu
19 Načini vezavnih poskusov Saturacija Inhibicija Kinetika
20 Parametri, ki jih dobimo z Saturacijski poskusi določitev B max in K D vezavnimi poskusi Kinetični poskusi določitev K a in K d (K d / K a =K D ) Inhibicijski poskusi določitev IC 50
21 Celokupna vezava =[A*] B max /([A*] + K D ) + k[a*] Nespecifična vezava nsv = k [A*] Specifična vezava (celokupna nespecifična = specifična) = = [A*]/ [A*] + K D
22 Celokupna vezava Vezava v prisotnosti antagonista 100 x K D
23 Kinetična vezavna študija časovni potek Ravnotežje, saturabilnost, reverzibilnost
24 Primer saturacijske vezavne študije
25 Neposredni in Scatchardov prikaz vezavne študije
26 Napake, ki nastanejo pri transformaciji podatkov
27 Inhibicijske vezavne študije Cilji: določiti IC 50, koncentracijo liganda, ki prepreči 50% specifične vezave radioliganda
28 Inhibition of specific binding of 3 H-mepyramine to guinea pig myocardial membranes with 2-phenylhistamine derivatives 100 % of inhibition of specific 3 H-mepyramine binding IPH 2-BPH histamine 2-CPH 2-FPH 2-PH log conc. agonist Each dot represents the mean of 3-5 independent experiments made in triplicate. The SEM value is not greater than 5 %. Abbreviations see Methods, subsection Drugs.
29 % inhibition of specific binding log conc. histamine log conc. 2-IPH The influence of GTP (0.1 mm) on the competition binding of 2- phenylhistamine derivatives to 3 H-mepyramine labeled H1- receptor in vascular smooth muscle membranes % inhibition of specific binding log conc. 2-BPH log conc. 2-CPH % inhibition of specific binding log conc. 2-triFMPH log conc. 2-FPH
30 HN R N NH2 Comparison of affinities of histamine and 2-phenylhistamine derivatives for H1- receptor binding sites in vascular and cardiac tissue and influence of GTP (0.1 mm) on the potency vascular membranes cardiac membranes R H F CF 3 Cl Br I 2-PH a compaund c 2-FPH a 2-triFMPH a 2-CPH a 2-BPH a 2-IPH a + GTP b + GTP b + GTP b + GTP b + GTP b + GTP b histamine a + GTP b pk i R H (high affinity site) 9.14 (66 %) * 8.46 (69 %) * 8.04 (81 %) * 8.40 (40 %) * 8.13 (45 %) * * * 7.38 (55 %) * pk i R L (low affinity site) 7.70 (34 %) (31 %) (19 %) (60 %) (55 %) (45 %) 5 98 pk i R H (high affinity site) * n.d (44 %) 9.80 (30 %) 9.82 (60 %) * 8.87 (50 %) pk i R L (low affinity site) 7.11 n.d (50 %) 8.19 (70 %) 8.05 (40 %) (50 %) * not detected n.d. not determined a derived from displacement curves shown on Fig. 1 and Fig. 2. The reported pk i values indicate that the binding data were best fitted according to a two binding site model using the non-linear curve fitting. Displacement binding curves were monophasic for 2-PH in both tissues and 2-FPH in cardiac tissue. b derived from displacement curves shown on Fig. 3 or not shown R H and R L are percentages of receptor high and low affinity states. c order of lipophilicity : 2-triFMPH > 2-IPH > 2-BPH > 2-CPH > 2-FPH >> 2-PH Abbreviations see Methods, subsection Drugs.
31 Inhibicijske vezavne študije z nekompetitivnim antagonistom
32 Primer, ko se antagonist veže na dve vezavni mesti
33 Vpliv dveh stanj receptorjev sklopljenih s proteinom G
34
35 Slabosti Ne dogajajo se v realnem času Upoštevati moramo tkivo različne afinitete na celih celicah in izoliranih membranah Vezavne študije s fluorescentnimi ligandi
36 Opredelitev receptorja Ime receptorja Druga imena - sinonimi Endogeni agonist (?) Identifikacijska številka v Ensembl ID bazi Glavni transdukcijski signal Velikostni red afinetet/moči posameznih ligandov Selekivni agonisti Selektivni antagonisti Radioaktivni ligandi Gen (?)
37 MOLEKULARNO-BIOLOŠKE METODE
38 Astrociti vzgojeni iz možganske skorje neonatalnih podgan in vzgojeni v kulturi
39
40 Tabela 3.1: Pari oligonukleotidnih začetnikov za 5-HT receptorje in ciklofilin ter velikost produkta RT-PCR receptor istosmerni oligonukleotidni začetnik (reverse primer) obratnosmerni oligonukleotidni začetnik (forward primer) 5-HT 1A CTCCTTGGCGGTTACTGAT GTAGATGGTGTAGCCGTGGT HT 1B TGATGCGGTGGACTATTCTG ACCGTGGAGTAGACCGTGTAGA HT 1D GCATCTCTGTGTCATCGCTCT ATGTGTTCACCAGGCAGTCA HT 1F AGCAATCACAGACGCAGT GCCATTCAGTTCCTCCTT HT 2A GGCATCGTGTTCTTCCTGTT TCAGCATCTTCCTGTGAGTTCT HT 2B CTCCGAAGTTCAACCATTCAGTC TTGCTTGCGTCCTCCTCATC HT 2C TCCTTCGTGGCATTCTTC ACACACATAGCCAATCCACA HT 3 ATGGCTCTGCTGGTGATAA TCAGTCTTGTTGGCTTGG HT 4 GGAACAACATCGGCATAGT TGATATAGCCAAGCCAGAGG HT 5A ATGGCTATCTCGGATGTGCTA CGACTGACCTGGCATTCTTC HT 5B GACTCCTTGACATAGCCTCTC TACTGAGCCATCTTGACGAC HT 6 ATCCTCAACCTCTGCCTCAT CTTCCTGCTATGCTTGGTG HT 7 AATCATTGGCTGAGACTGC CACTCTTGTGGATGTGGACT 278 ciklofilin TGGACCAAACACAAATGGTT TGATCTTCTTGCTGGTCTT 161 velikost produkta v baznih parih
41 mrna podtipov serotoninskih receptorjev v možganski skorji in astrocitih vzgojenih in možganske skorje 3 dni stare podgane Slika 4.2. Tkivni homogenati (a) in kulture astrocitov (b) skorje velikih možganov novorojene podgane: fotografija elektroforeznega gela, obarvanega z etidijevim bromidom, ki kaže produkte RT-PCR različnih mrna za serotoninske receptorje. Ustrezne dolžine produktov v baznih parih (bp) so prikazane v Tabeli 3.1. Kot pozitivno kontrolo smo uporabili gen za ciklofilin, ki se vedno in povsod izraža.
42 mrna podtipov serotoninskih receptorjev v možganski skorji in astrocitih vzgojenih in možganske skorje 3 dni stare in odrasle podgane
43 Imunohistokemično barvanje receptorja 5-HT 5A (A) in GFAP (B)
44 Structure of the human histamine H1 receptor complex with doxepin. Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S. Nature Jun 22;475(7354):65-70.
45
46 G protein cycle for the 2 AR Gs complex. SGF Rasmussen et al. Nature 000, 1-7 (2011) doi: /nature10361 Note: This figure is from a near-final version AOP and may change prior to final publication in print/online
47 Overall structure of the 2 AR Gs complex. SGF Rasmussen et al. Nature 000, 1-7 (2011) doi: /nature10361 Note: This figure is from a near-final version AOP and may change prior to final publication in print/online
48 Comparison of active and inactive 2 AR structures. SGF Rasmussen et al. Nature 000, 1-7 (2011) doi: /nature10361 Note: This figure is from a near-final version AOP and may change prior to final publication in print/online
49 Receptor-G protein interactions. SGF Rasmussen et al. Nature 000, 1-7 (2011) doi: /nature10361 Note: This figure is from a near-final version AOP and may change prior to final publication in print/online
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