-identify variations as compared to progesterone (explore chirality of molecule?) -identify receptor -find a paper: why do these areas of receptor bind to Mifepristone better than progesterone? what is the implication? -build drug on Gaussian and run calculations
NOTES: searched J or Org Chem, J Med Chem. Two articles returned about derivatives of Mife. The biological activity of progesterone is mediated by progesterone receptor (PR). androgen receptor- ligand-regulated transcription factor Mife: antiprogesterone, antiglucocorticoid (inhibits anti-inflammation?), antiandrogen dimethylaniline substituent at 11B position thought to interfere with gene expression by dislodging the activation helix of PR, GR, AR.
-find definitive mechanisms of action of Mifepristone (see paper: RU486: Mechanisms of Action and Clinical Uses) ... how does drug get t specific receptor sites? where are these receptor sites? (cell surface?) -Locate book via ILL: "Adrenal Steroid Antagonism" for description of molecule-receptor interactions upon discovery of drug. -how is it used as both a contraceptive and pregnancy termination drug? -examine Gaussian calculations- if possible
SET UP A TIME AND WE CAN LOOK AT THE GAUSSIAN RESULTS
week of 10/8/07:
We viewed and examined the Gaussian results to find the HOMO and LUMO of mifepristone. Going forward, it would be interesting, and perhaps necessary, to compare these to the HOMO and LUMO of progesterone. I have decided to focus on the Progesterone Receptor of Mifepristone, as it apparently can bind to the PR, glucocorticoid receptor, or the androgen receptor. Given the multiplicity of uses for Mifepristone, I have also decided to focus specifically on its uses as a contraceptive and as an "abortion pill."
Specific items to explore this week: -the normal binding of progesterone to its receptor- see steroidal receptor chapter in book. -the normal cascade of events that is initiated by progesterone binding -the amino acids that bind to progesterone/mifepristone at the places of variation, and their properties. -look up: Chime protein explorer at UMass for these amino acids and their active sites.
Looking ahead: partial agonist properties --- what cascade is intitiated by mifepristone, if any? refining broader questions: BC v abortion, analog with endogenous hormone (perhaps that initiates miscarriages?) side effects/outside effects? -- what is the big picture? what is consequence of alkyne group on steroid structures?
week of 10/15/07:
MEETING TIME: 1:30 WED
I found two major articles that helped clarify my search in understanding the different uses of Mifepristone: "Mechanisms of action of mifepristone and levonorgesterol when used for emergency contraception" and "Early pregancy termination with Mifepristone and Misoprostol in the United States."
I looked up the amino acids responsible for the binding sites at the variations between the progesterone and mifepristone molecule.
Two other articles to which I could not gain full access also seemed helpful: "Emergency Postcoital Contraception" and " Contraceptive use of antiprogestins"
A final article this week that may be promising: "Pharmokinetic Study of RU 486 and its metabolites after oral administration of single doses to pregnant and non-pregnant women."
I have read up on the normal cascade of events that occurs as a result of progesterone binding to the PR. The sources used for this were the Cell Bio textbook as well as the Medicinal Chemistry text. This helped me to understand why the use of Mifepristone would be needed in different amounts as a contraceptive, as a "morning after pill," or as an abortion pill. I also now understand why mifepristone is only a successful terminator at a certain time frame, early in pregnancy.
Synthetic progestins, such as Mifepristone, require the following: a ring for binding (as is found in all steroidal derivatives), and an alkyl group, which "slows metabolism," though I do not know the chemical mechanism behind this. Finally, adding a methyl or a chloro substituent (Mife. has a methyl group added near the alkyne) apparently "enhances bioactivity and slows metabolism."
All of this is important when designing the drug Mife because regular progesterone has only a 5 minute half life in serum, compared with Mifepristone's half life of 25- 30 hours.
Going forward, I am still unclear as to the chemical process by which Mifepristone is bound, and I also do not have the specifics of this process for progesterone.