Oppgave

Når f.eks. en agonist bindes til en reseptor uttrykker vi graden av binding i verdien "occupancy" som benevnes pAR. pAR kan beregnes hvis man kjenner likevektskonstanten for bindingen mellom agonist og reseptor og konsentrasjonen av agonist (se ligningen 1.2).

a) Forklar med egne ord hvorfor benevningen for KA blir M.

Å fastslå en sikker verdi for konsentrasjonen av A, kan være et stort problem.

b) Nevn kort noen årsaker til dette.

c) Studer følgende figurer:

1.5, 1.6, 1.7, 1.18, 1.19, 1.21, 1.23, 1.26

og tabell 1.1 og 1.2

d) Thromb Haemost. 2000 Nov;84(5):891-6.

Studer abstract under:
Identification and biological activity of the active metabolite of clopidogrel.
Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM.

Like ticlopidine, the ADP receptor antagonist clopidogrel is inactive in vitro and must be administered i.v. or orally to exhibit antiaggregatory and antithrombotic activities. We have previously shown that hepatic metabolism is necessary for activity. This study demonstrates that an active metabolite can be generated from human liver microsomes incubated with clopidogrel. Using several analytical methodologies (LC/MS, NMR, chiral supercritical fluid chromatography), we have identified its structure. In vitro, this highly unstable compound, different from that formed from ticlopidine, exhibited all the biological activities of clopidogrel observed ex vivo: Irreversible inhibition of the binding of 33P-2MeS-ADP to washed human platelets (IC50) = 0.53 microM), selective inhibition of ADP-induced platelet aggregation (IC)50 = 1.8 microM) and ADP-induced adenylyl cyclase down-regulation. The irreversible modification of the ADP-receptor site which is responsible for the biological activity could be explained by the formation of a disulfide bridge between the reactive thiol group of the active metabolite and a cysteine residue of the platelet ADP receptor.

(33P-2MeS-ADP er en ADP-analog)

Spørsmål:

-Er clopidogrel en prodrug?
-Er den aktive metabolitten kompetitiv eller non-kompetitiv?
-Er interaksjonen med reseptor reversibel eller irreversibel?
-Hvordan måles ADPs effekt på platene?
-Foreligger det indikasjoner på reseptoroverskudd?