Prostaglandin F2alpha

Prostaglandin F2α (PGF2α in prostanoid nomenclature), pharmaceutically termed carboprost is a naturally occurring prostaglandin used in medicine to induce labor and as an abortifacient.[1] Prostaglandins are lipids throughout the entire body that have a hormone-like function.[2] In pregnancy, PGF2 is medically used to sustain contracture and provoke myometrial ischemia to accelerate labor and prevent significant blood loss in labor.[3] Additionally, PGF2 has been linked to being naturally involved in the process of labor. It has been seen that there are higher levels of PGF2 in maternal fluid during labor when compared to at term.[4] This signifies that there is likely a biological use and significance to the production and secretion of PGF2 in labor. Prostaglandin is also used to treat uterine infections in domestic animals.

This article is about the pharmaceutical agent 'dinoprost'. For the drug 'dinoprostone', see Prostaglandin E2.
Dinoprost
Clinical data
Other namesAmoglandin, Croniben, Cyclosin, Dinifertin, Enzaprost, Glandin, PGF2α, Panacelan, Prostamodin
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Intravenous (cannot used to induce labor)because it cannot be used in cervix, intra-amniotic (to induce abortion)
ATC code
Pharmacokinetic data
Elimination half-life3 to 6 hours in amniotic fluid, less than 1 minute in blood plasma
Identifiers
  • (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)- 3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.209.720
Chemical and physical data
FormulaC20H34O5
Molar mass354.487 g·mol−1
3D model (JSmol)
Solubility in water200 mg/mL (20 °C)
  • O=C(O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC
  • InChI=1S/C20H34O5/c1-2-3-6-9-15(21)12-13-17-16(18(22)14-19(17)23)10-7-4-5-8-11-20(24)25/h4,7,12-13,15-19,21-23H,2-3,5-6,8-11,14H2,1H3,(H,24,25)/b7-4-,13-12+/t15-,16+,17+,18-,19+/m0/s1 ☒N
  • Key:PXGPLTODNUVGFL-YNNPMVKQSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

In domestic mammals, it is produced by the uterus when stimulated by oxytocin, in the event that there has been no implantation during the luteal phase. It acts on the corpus luteum to cause luteolysis, forming a corpus albicans and stopping the production of progesterone. Action of PGF2α is dependent on the number of receptors on the corpus luteum membrane.

The PGF2α isoform 8-iso-PGF2α was found in significantly increased amounts in patients with endometriosis, thus being a potential causative link in endometriosis-associated oxidative stress.[5]

Mechanism of action
Further information: Prostaglandin F2α receptor

PGF2α acts by binding to the prostaglandin F2α receptor. It is released in response to an increase in oxytocin levels in the uterus, and stimulates both luteolytic activity and the release of oxytocin.[6] Because PGF2α is linked with an increase in uterine oxytocin levels, there is evidence that PGF2α and oxytocin form a positive feedback loop to facilitate the degradation of the corpus luteum.[7] PGF2α and oxytocin also inhibit the production of progesterone, a hormone that facilitates corpus luteum development. Conversely, higher progesterone levels inhibit production of PGF2α and oxytocin, as the effects of the hormones are in opposition to each other. This is directly exhibited following ovulation when there is a spike of progesterone levels, and then as progesterone levels decrease, PGF2 levels will peak.[8]

Pharmaceutical Use

When injected into the body or amniotic sac, PGF2α can either induce labor or cause an abortion depending on the concentration used. In small doses (1–4 mg/day), PGF2α acts to stimulate uterine muscle contractions, which aids in the birth process. However, during the first trimester and in higher concentrations (40 mg/day),[9] PGF2α can cause an abortion by degrading the corpus luteum, which normally acts to maintain pregnancy via the production of progesterone. Since the fetus is not viable outside the womb by this time, the lack of progesterone leads to the shedding of the uterine lining and the death of the fetus. However, this process is not fully understood.

Pyometra and uterine infections
Bottle of Lutalyse® injectable

Lutalyse is used for the treatment of pyometra in domestic dogs and cats.[10] The drug is also administered to dairy cows in order to reduce uterine infections.[11]

Synthesis

Industrial Synthesis

In 2012 a concise and highly stereoselective total synthesis of PGF2α was described.[12] The synthesis requires only seven steps, a huge improvement on the original 17-steps synthesis of Corey and Cheng,[13] and uses 2,5-dimethoxytetrahydrofuran as a starting reagent, with S-proline as an asymmetric catalyst.

In 2019, a more effective and stereoselective synthesis was described.[14] The synthesis requires 5 steps to get to the intermediate which then undergoes a cross-metathesis reaction to install the E-alkene. Then, a Wittig reaction is performed to install the Z-alkene. Finally, the protecting groups are removed with acid.

In the body PGF2α is synthesized in several distinct steps. First, Phospholipase A2 (PLA2) facilitates the conversion of phospholipids to Arachidonic Acid, the framework from which all prostaglandins are formed.[15] The Arachidonic Acid then reacts with two Cyclooxygenase (COX) receptors, COX-1 and COX-2, or PGH synthase to form Prostaglandin H2, an intermediate.[15] Lastly, the compound reacts with Aldose Reductase (AKR1B1) or PGF Synthase to form PGF2α.[15]

Analogues

The following medications are analogues of prostaglandin F2α:

References
  1. O'Neil MJ, ed. (2013). The Merck index: an encyclopedia of chemicals, drugs, and biologicals (15th ed.). Cambridge, UK: Royal Society of Chemistry. ISBN 978-1849736701. OCLC 824530529.
  2. "Prostaglandin". Britannica. September 28, 2022. Retrieved November 6, 2022.
  3. Kerekes L, Domokos N (July 1979). "The effect of prostaglandin F2 alpha on third stage labor". Prostaglandins. 18 (1): 161–166. doi:10.1016/S0090-6980(79)80034-9. PMID 392622.
  4. Sahmay S, Coke A, Hekim N, Atasu T (1988). "Maternal, umbilical, uterine and amniotic prostaglandin E and F2 alpha levels in labour". The Journal of International Medical Research. 16 (4): 280–285. doi:10.1177/030006058801600405. PMID 3169373. S2CID 73028858.
  5. Sharma I, Dhaliwal LK, Saha SC, Sangwan S, Dhawan V (June 2010). "Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis". Fertility and Sterility. 94 (1): 63–70. doi:10.1016/j.fertnstert.2009.01.141. PMID 19324352.
  6. Samuelsson B, Goldyne M, Granström E, Hamberg M, Hammarström S, Malmsten C (1978). "Prostaglandins and thromboxanes". Annual Review of Biochemistry. 47: 997–1029. doi:10.1146/annurev.bi.47.070178.005025. PMID 209733.
  7. Hooper SB, Watkins WB, Thorburn GD (December 1986). "Oxytocin, oxytocin-associated neurophysin, and prostaglandin F2 alpha concentrations in the utero-ovarian vein of pregnant and nonpregnant sheep". Endocrinology. 119 (6): 2590–2597. doi:10.1210/endo-119-6-2590. PMID 3465529.
  8. Downie J, Poyser NL, Wunderlich M (January 1974). "Levels of prostaglandins in human endometrium during the normal menstrual cycle". The Journal of Physiology. 236 (2): 465–472. doi:10.1113/jphysiol.1974.sp010446. PMC 1350813. PMID 16992446.
  9. "Dinoprost tromethamine Injection Advanced Patient Information". Truvn Health Analytics Inc. 2016. Retrieved November 2, 2017.
  10. Davidson AP, Feldman EC, Nelson RW (March 1992). "Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990)". Journal of the American Veterinary Medical Association. National Library of Medicine. 200 (6): 825–828. PMID 1568932. Retrieved 2 December 2021.
  11. Menino A. "Evaluation of Single Lutalyse Injection Protocol to Reduce Uterine Infections and Improve Reproductive Efficiency in Postpartum Dairy Cows". USDA. OREGON STATE UNIVERSITY. Retrieved 2 December 2021.
  12. Coulthard G, Erb W, Aggarwal VK (September 2012). "Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps". Nature. 489 (7415): 278–281. Bibcode:2012Natur.489..278C. doi:10.1038/nature11411. PMID 22895192. S2CID 205230275.
  13. Corey EJ, Cheng XM (1995). The Logic of Chemical Synthesis. Wiley.
  14. Kim T, Lee SI, Kim S, Shim SY, Ryu DH (2019). "Total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α via three-component coupling". Tetrahedron. 75 (42): 130593. doi:10.1016/j.tet.2019.130593. S2CID 203131829.
  15. Fortier MA, Krishnaswamy K, Danyod G, Boucher-Kovalik S, Chapdalaine P (August 2008). "A postgenomic integrated view of prostaglandins in reproduction: implications for other body systems". Journal of Physiology and Pharmacology. 59: 65–89. PMID 18802217.
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