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Prostaglandin F2alpha
Prostaglandin F2alpha
Prostaglandin F2alpha
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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 Edit this at Wikidata
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)

Prostaglandin F2α (PGF2α in prostanoid nomenclature), pharmaceutically termed dinoprost, 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, PGF2α is medically used to sustain contracture and provoke myometrial ischemia to accelerate labor and prevent significant blood loss in labor.[3] Additionally, PGF2α has been linked to being naturally involved in the process of labor. It has been seen that there are higher levels of PGF2α 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 PGF2α in labor. Prostaglandin is also used to treat uterine infections in domestic animals.

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

[edit]
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, PGF2α levels will peak.[8]

Pharmaceutical Use

[edit]

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

[edit]
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

[edit]

Industrial Synthesis

[edit]

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-step synthesis of Corey,[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] 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 or prostaglandin F synthase to form PGF2α.[15]

Analogues

[edit]

The following medications are analogues of prostaglandin F2α:

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Prostaglandin F2alpha

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from Grokipedia
(PGF₂α), also termed dinoprost, is a naturally occurring lipid mediator derived from via the pathway, characterized by its C₂₀H₃₄O₅ and a featuring hydroxyl groups at positions 9α, 11α, and 15S on a prostanoic acid backbone. It primarily functions by binding to the prostaglandin F receptor (PTGFR or FP receptor), a that triggers activation, increasing intracellular calcium and promoting contraction. PGF₂α plays a central role in reproductive , inducing luteolysis—the regression of the —to facilitate the return to estrus and ovarian cyclicity in mammals, as well as stimulating myometrial contractions essential for parturition. In non-reproductive contexts, it contributes to , , and regulation of . Pharmaceutically, synthetic PGF₂α or its tromethamine salt is employed as an and oxytocic agent in humans for second-trimester pregnancy termination, while analogs like treat postpartum hemorrhage by controlling uterine bleeding through potent effects. In , PGF₂α formulations such as dinoprost tromethamine are widely used for estrus synchronization in , enabling efficient breeding management by reliably inducing luteolysis after day 5 of the . Receptor agonists derived from PGF₂α, including latanoprost, are staples in for lowering in patients via enhanced uveoscleral outflow. Despite its efficacy, direct use of PGF₂α can provoke side effects like gastrointestinal distress and due to systemic stimulation, often necessitating analog modifications for clinical tolerability.

Discovery and History

Initial Identification and Early Studies

Prostaglandin F2α (PGF2α) was first isolated from sheep glands in 1960 by and colleagues, who employed chromatographic separation and bioassay-guided purification to identify the compound's . This isolation followed earlier work on from seminal fluid, where PGF2α was detected in human semen samples using similar extraction methods from the late , confirming its presence in reproductive tissues. Structural characterization was completed by 1963 through degradation studies and spectroscopic analysis, distinguishing PGF2α from PGE compounds by its and hydroxyl group configuration. Initial studies in the early 1960s utilized bioassays on isolated preparations, such as strips of duodenum and ileum, to quantify PGF2α's contractile potency, which was found to be comparable to or exceeding that of at nanomolar concentrations. These empirical tests, grounded in direct measurement of tissue responses, established PGF2α's role in modulating tone, with applications to uterine and vascular tissues in animal models. In sheep and human uterine homogenates, PGF2α was subsequently extracted and quantified via precursors, revealing elevated levels during the , suggesting involvement in reproductive cyclicity. By 1972, experiments in sheep demonstrated PGF2α's luteolytic effects, with intra-arterial infusions into the causing rapid regression of the and a decline in progesterone within hours, as measured by venous sampling. McCracken et al. linked uterine-derived PGF2α, released in pulses during non-pregnant cycles, to local action on the ipsilateral via counter-current exchange in the utero-ovarian vasculature, supported by unilateral infusion studies showing site-specific luteolysis without systemic effects. These findings, derived from ovariectomized and autotransplanted models in sheep, provided causal evidence for PGF2α's role in terminating the , contrasting with earlier nonspecific observations of activity.

Development as a Therapeutic Agent

Research on , including prostaglandin F2α (PGF₂α), stagnated after initial discoveries in due to challenges in isolation and synthesis, but was reinitiated in 1963 by with a focus on luteolytic effects for reproductive management in . By 1973, experimental data confirmed PGF₂α's ability to induce luteolysis in , enabling the development of estrous protocols that regress the and facilitate timed breeding. These milestones addressed key barriers in adoption, such as variable estrus timing, though early studies highlighted dose-dependent variability in response rates. The U.S. (FDA) approved dinoprost tromethamine, the tromethamine salt of PGF₂α marketed as Lutalyse, in 1976 for veterinary applications in , initially for inducing in feedlot heifers and later expanded to estrous in breeding herds. testing demonstrated that a single intramuscular dose of 25 mg (5 mL) in estrous-cycling with a functional typically induces estrus within 2-5 days, with rates exceeding 80% when combined with detection protocols. Applications extended to mares, where doses of 2.5-5 mg effectively shortened diestrus and supported breeding management, despite occasional challenges like incomplete luteolysis in some animals. In , PGF₂α (dinoprost) advanced to clinical trials in the early 1970s for and as an , with FDA approval for these indications achieved by the late 1970s; however, its adoption was limited by adverse effects including and gastrointestinal distress, leading to preference for alternative agents like E analogs. Regulatory scrutiny and post-approval monitoring underscored the need for careful patient selection to mitigate risks in therapeutic deployment.

Chemical Structure and Properties

Molecular Structure

Prostaglandin F2α (PGF2α), also known as dinoprost, has the molecular formula C20H34O5 and features a central cyclopentane ring substituted with two side chains: an α-chain consisting of a heptenoic acid with a cis double bond between carbons 5 and 6, and an ω-chain with a trans double bond between carbons 13 and 14 bearing a hydroxyl group at carbon 15. The cyclopentane ring includes hydroxyl groups at positions 9α and 11α, contributing to its characteristic F-series configuration. The stereochemistry of PGF2α is defined by the IUPAC name (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]cyclopentyl]hept-5-enoic acid, with specific configurations at chiral centers C8(R), C9(S), C11(R), C12(S), and C15(S) that are essential for biological activity. These stereocenters have been elucidated through spectroscopic methods including NMR and confirmed in receptor binding studies, where alterations disrupt interactions with the FP receptor. In comparison to prostaglandin E2 (PGE2), which possesses a ketone group at C9 and a hydroxyl at C11, the dual α-hydroxyls at C9 and C11 in PGF2α enable selective binding to the prostaglandin F receptor (FP), distinct from PGE2's affinity for EP receptors, as evidenced by conformational analyses showing differential hydrogen bonding networks around the cyclopentane ring.

Physical and Chemical Characteristics

Prostaglandin F2α (PGF2α) is typically isolated as a colorless to pale yellow viscous oil or low-melting solid with a reported melting point of 25–35 °C. Its specific optical rotation is [α]D25 +23.5° (c = 1 in tetrahydrofuran), reflecting the chirality at multiple stereocenters. The estimated density is 1.046 g/cm³, and the boiling point is approximately 408 °C under reduced pressure, though practical handling avoids such conditions due to thermal instability. Solubility characteristics are critical for formulation: PGF2α free acid shows high solubility (>100 mg/mL) in organic solvents including ethanol, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), but limited aqueous solubility necessitates salt forms like tromethamine for enhanced water solubility up to 200 mg/mL. Its amphiphilic profile, with a lipophilic hydrocarbon backbone and polar hydroxyl/carboxyl groups, supports membrane permeability despite ionization of the carboxylic acid at neutral pH, yielding a log Do/w much less than 1 in physiological media. Stability is pH-dependent, with greater resilience in acidic environments compared to neutral or basic conditions, where exposure risks , at the C13–C14 , or oxidative degradation of allylic alcohols, dictating storage as ethanolic solutions at -20 °C under inert atmosphere. Analytical identification employs spectral properties: UV absorbance peaks near 217 nm from the conjugated (ε ≈ 26,000–28,000 M-1 cm-1 in ); IR spectroscopy reveals O–H stretches at 3300–3500 cm-1, C=O at ≈1710 cm-1 (carboxyl), and C=C at 1650–1680 cm-1; 1H NMR in D2O or CDCl3 displays characteristic multiplets for the protons (δ 0.8–2.5 ppm), olefinic signals (δ 5.2–5.6 ppm), and hydroxyl exchanges (δ 2–5 ppm, solvent-dependent).

Biosynthesis and Metabolism

Endogenous Biosynthetic Pathway

Prostaglandin F2α (PGF2α) is synthesized endogenously from arachidonic acid (AA), a polyunsaturated fatty acid released from membrane phospholipids by phospholipase A2 (PLA2) enzymes in response to cellular stimuli. The committed step involves the conversion of AA to prostaglandin H2 (PGH2), the common precursor for all prostaglandins, catalyzed by cyclooxygenase enzymes (COX-1 and COX-2). COX-1 provides constitutive basal production, while COX-2 is inducible and upregulated during inflammatory or hormonal signals, performing both cyclooxygenation to form PGG2 and peroxidation to yield PGH2. PGF2α formation from PGH2 occurs primarily via reduction by prostaglandin F synthase (PGFS), an enzyme belonging to the aldo-keto reductase family such as AKR1C3, which directly reduces the 9-keto group of PGH2. An alternative pathway involves isomerization of PGH2 to PGE2 by prostaglandin E synthase, followed by reduction of PGE2 to PGF2α via PGE2 9-ketoreductase activity, often mediated by the same AKR enzymes. This is localized predominantly in uterine endometrial cells, pulmonary tissues, and intra-luteal cells, with tissue-specific expression of PGFS and COX-2 driving production rates. Biosynthesis is tightly regulated by hormones, particularly in reproductive tissues. In the uterus, oxytocin stimulates PGF2α secretion by enhancing PLA2 activity and COX-2 expression, with responsiveness peaking during luteolysis when pulsatile uterine PGF2α output surges to induce corpus luteum regression. Quantitative data from ruminant models show that during luteolysis, endometrial PGF2α synthesis yields pulses of 200–500 ng/min in cattle, sufficient to reduce luteal progesterone by over 50% within hours via feedback on luteal COX-2. In non-reproductive contexts, such as lungs, basal production supports vascular tone, modulated by shear stress-induced COX-2 without prominent hormonal oversight.

Degradation and Elimination

Prostaglandin F2α is primarily inactivated through oxidation of its 15α-hydroxyl group by the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), yielding the biologically inactive 15-keto-PGF2α. This rate-limiting step occurs predominantly in the lungs upon passage through the , with additional contributions from , liver, and other tissues expressing 15-PGDH. Subsequent reduction of the Δ¹³ by 13,14-prostaglandin reductase produces 13,14-dihydro-15-keto-PGF2α (PGFM), the major circulating metabolite used as a for PGF2α production. Further degradation involves β- and ω-oxidation, leading to chain-shortened metabolites like tetranor derivatives. The plasma half-life of endogenous PGF2α is extremely brief, on the order of seconds to 1 minute during the initial distribution phase, owing to swift pulmonary uptake and enzymatic inactivation. Terminal elimination for the parent compound extends to approximately 9–26 minutes across , encompassing clearance. These short durations preclude significant accumulation under physiological conditions, with varying by dose, , and administration route; for instance, intravenous bolus yields faster distribution than endogenous release. Elimination of PGF2α metabolites occurs mainly via renal excretion into , where PGFM and downstream products predominate, representing over 85% of output in some models; minor fecal elimination accounts for the remainder through biliary routes. Urinary levels of these metabolites serve as reliable indicators of systemic PGF2α turnover due to their stability relative to the parent . Factors affecting clearance include pulmonary blood flow and 15-PGDH activity, which can be modulated by or inhibitors, while renal function influences ; hepatic involvement is secondary, as primary is extrahepatic. In conditions impairing or function, half-lives may prolong modestly, but the rapid initial inactivation minimizes risks of prolonged activity.

Mechanism of Action

Prostaglandin F2α (PGF2α) primarily mediates its biological effects through binding to the FP receptor, a rhodopsin-like (GPCR) expressed in various tissues including , , and ocular tissues. The FP receptor exhibits high selectivity for PGF2α over other prostaglandins, as revealed by cryo-electron structures showing specific ligand-receptor interactions that stabilize the active conformation and dictate coupling preferences. Upon binding, the receptor undergoes conformational changes that facilitate engagement, predominantly Gq/11 subtypes. This Gq-coupled activation stimulates C-β (PLC-β), which catalyzes the hydrolysis of (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors on the , triggering calcium release into the and elevating intracellular Ca2+ concentrations, a key event driving downstream responses such as myometrial contraction and luteolysis. DAG, in turn, recruits and activates (PKC) isoforms, which phosphorylate targets leading to (MAPK) pathway activation, including extracellular signal-regulated kinase (ERK) and p38 MAPK, thereby amplifying signaling for , , or depending on context. In certain systems, FP receptor signaling can crosstalk with other pathways, such as β-catenin stabilization or EGFR transactivation, modulating via T-cell factor (Tcf) transcription factors.

Physiological Functions

Reproductive Physiology

Prostaglandin F2α (PGF2α) induces luteolysis, the functional and structural regression of the (CL), in many mammalian species through binding to FP receptors on luteal endothelial and steroidogenic cells, triggering that reduces blood flow and oxygen delivery, followed by via extrinsic death receptor pathways and mitochondrial dysfunction. In ruminants such as and sheep, uterine pulses of PGF2α—typically 2–5 pulses of 200–500 pg/mL in peripheral plasma—are transported to the ipsilateral via counter-current exchange in utero-ovarian veins, ensuring targeted CL regression in non-pregnant cycles. This process declines progesterone production by over 90% within 24–48 hours, enabling follicular development for the next . The luteolytic mechanism is conserved across domestic livestock species, including sheep and , where endometrial PGF2α synthesis, stimulated by oxytocin pulses from the CL, forms a feedback loop essential for timely CL demise absent embryonic antiluteolytic signals like interferon-tau. In sheep, peak luteolytic PGF2α pulses coincide with declining progesterone, with plasma concentrations rising to 300–600 pg/mL during regression. During parturition, PGF2α surges contribute to myometrial contractions and cervical remodeling across . In humans, maternal plasma PGF2α levels rise progressively in the third trimester, reaching 2–3-fold elevations before labor onset and further increasing 10–30-fold during active labor to promote receptor-mediated calcium influx and actin-myosin interactions in uterine . In , prepartum PGF2α pulses (up to 1–2 ng/mL) coordinate with oxytocin to enhance contractility, while in sheep, similar surges facilitate expulsion without dominant roles in where PGE2 predominates for ripening. Empirical data from peripheral and uterine venous sampling confirm these dynamics, underscoring PGF2α's role in amplifying labor progression via direct myometrial sensitization rather than initiation.

Non-Reproductive Roles

Prostaglandin F2α (PGF2α) exerts effects on beyond reproductive tissues, notably inducing through contraction of bronchial via activation of FP receptors. Inhalation of PGF2α triggers dose-dependent airway narrowing, with asthmatic individuals demonstrating approximately 8,000-fold greater sensitivity compared to healthy subjects, as measured by reductions in forced expiratory volume. This response involves receptor mediation and downstream signaling via intracellular calcium and pathways, contributing to pulmonary as well. PGF2α also modulates vascular tone by promoting constriction in vascular cells, often through FP receptor-coupled /11 signaling that elevates intracellular calcium and activates Rho-kinase pathways. This leads to enhanced contractility, as observed in coronary and systemic vessels, where PGF2α amplifies responses to other vasoconstrictors like endothelin-1 via C-dependent mechanisms. In renal vasculature, PGF2α supports by regulating afferent arteriolar tone and influencing salt and water balance, with disruptions in FP receptor signaling linked to altered control in preclinical models. In inflammatory contexts, PGF2α participates in local responses, including elevated secretion from tissues like the , though its potency is generally lower than that of PGE2, which more prominently coordinates proinflammatory and cascades. Experimental evidence from FP receptor studies indicates PGF2α's role in amplifying and in inflamed vascular , potentially exacerbating chronic inflammation via generation. Regarding ocular physiology, PGF2α influences anterior segment responses by mediating sensory nerve-dependent hyperemia and contributing to inflammatory fluctuations in intraocular dynamics, independent of pressure-lowering effects. models of the FP receptor reveal preserved baseline ocular function but altered inflammatory responses, underscoring PGF2α's auxiliary role in non-pathological and uveitic-like conditions.

Medical Applications in Humans

Labor Induction and Pregnancy Termination

Prostaglandin F2α (PGF2α), administered as dinoprost, was historically used for second-trimester pregnancy termination through intra-amniotic instillation, typically at doses of 40 mg initially, with repeat doses every 24-48 hours if needed, achieving complete abortion in 85-93% of cases within 48 hours. Extra-amniotic infusion protocols, involving continuous or bolus delivery via catheter, demonstrated efficacy rates exceeding 90% for missed abortions, outperforming intravenous oxytocin in induction-delivery intervals. Intramuscular administration of analogs like 15-methyl PGF2α was also applied, with success in 44 of 61 midtrimester cases (72%), primarily between 13-17 weeks gestation. These methods induce myometrial contractions akin to endogenous PGF2α release during physiologic labor, but at supraphysiologic concentrations to overcome cervical rigidity in midtrimester gestations. Early clinical trials from the established PGF2α's role in elective second-trimester , with intra-amniotic protocols yielding expulsion rates of 80-95% without surgical intervention, though nulliparous patients required higher doses (up to 50 mg) for comparable outcomes to multiparous women. One study reported 100% complete rates with intra-amniotic PGF2α versus 96% for , highlighting its reliability in select cohorts despite longer mean induction times. Failure rates, defined as no expulsion within 24-48 hours, ranged from 7-15%, often necessitating adjunctive measures like tents or , with causal risks including retained products increasing hemorrhage or infection probability by 10-20% in incomplete cases. In comparisons to (PGE1 analog), PGF2α exhibited lower 24-hour success rates (72-86% versus 88-96%), longer intervals (mean 28-36 hours versus 12-24 hours), and higher failure incidences (up to 28% versus 12%), rendering it less efficient for routine use. 's advantages stem from enhanced cervical ripening and potency at lower doses, reducing the need for invasive administration; however, PGF2α remained viable where access was limited, with equivalent overall completion rates in resource-constrained settings. By the , declining adoption reflected these disparities, with PGF2α protocols largely supplanted except in specific fetal demise cases. For term , vaginal PGF2α gel was tested but yielded longer induction-delivery intervals than or PGE2, limiting its obstetric application.

Ocular and Glaucoma Treatment

Prostaglandin F2α analogues serve as first-line topical therapies for glaucoma and ocular hypertension by selectively activating the FP receptor, which promotes uveoscleral outflow of aqueous humor and thereby reduces intraocular pressure (IOP). This receptor-mediated mechanism involves cytoskeletal reorganization in outflow pathway cells and upregulation of matrix metalloproteinases, facilitating extracellular matrix remodeling without relying on conventional trabecular meshwork pathways. Unlike beta-blockers or alpha-agonists, these agents provide robust, sustained IOP lowering with once-daily dosing, minimizing compliance issues in chronic management. Latanoprost, the prototypical PGF2α analogue, received FDA approval on March 23, 1998, for treating elevated IOP in open-angle and . As a esterified for enhanced corneal penetration and stability, it hydrolyzes intracellularly to its active form, exerting effects primarily through FP receptor . Long-term studies confirm its role in delaying progression, with peak IOP reductions occurring within 8-12 hours post-administration and diurnal control persisting over years. Randomized clinical trials demonstrate latanoprost achieves mean IOP reductions of 25-35% from baseline, outperforming timolol in meta-analyses (30.2% vs. 26.9% at 3 months). For instance, in patients with , 2-week treatment yielded 32-34% drops, sustained over 2 years without . These outcomes stem from enhanced non-conventional outflow, verified via aqueous fluorophotometry and outflow facility measurements in human and animal models. Native prostaglandin F2α has limited direct ocular application due to its rapid enzymatic degradation, poor stability in topical formulations, and propensity for inducing conjunctival hyperemia and inflammation, prompting development of more tolerable analogues like latanoprost. While early experimental use showed IOP-lowering potential, clinical preference favors analogues for superior and side-effect profiles.

Other Human Uses

Prostaglandin F2α (PGF2α), administered as dinoprost, has been utilized in the of postpartum hemorrhage (PPH) through targeted delivery methods such as intrauterine irrigation. In cases of severe unresponsive to oxytocin, intrauterine instillation of PGF2α solutions (typically 0.2–1 mg in 20–50 mL saline) has achieved in a majority of patients, with one series reporting control of bleeding in 12 out of 13 women, thereby avoiding in most instances. This approach leverages PGF2α's potent myometrial contraction and vasoconstrictive effects on uterine vessels, though its use remains limited to specialized settings due to risks of systemic absorption leading to or . Investigational applications of PGF2α extend to dermatological contexts, where studies on hair follicles demonstrate stimulation of intermediate follicle growth via FP receptor activation, suggesting potential for treating androgenetic alopecia. Concentrations as low as 1–10 μg/mL promoted anagen phase prolongation and increased follicle length by up to 20%, independent of pigmentation effects seen with analogs like latanoprost. However, translation to trials is preliminary, hampered by side effect profiles including local and off-target smooth muscle effects. No large-scale clinical data support routine use. Early clinical explorations of PGF2α as an in the 1970s documented high efficacy for midtrimester termination, with extra-amniotic administration inducing complete in 89% of cases within 36 hours (mean interval 18 hours) at doses of 5–10 mg. Verifiable outcomes included a death-to-case of 10.5 per procedures, lower than contemporaneous saline methods but associated with gastrointestinal and respiratory adverse events prompting shifts to analogs. These historical data underscore PGF2α's potency while highlighting safety constraints that curtailed broader adoption beyond investigational contexts.

Veterinary Applications

Reproductive Synchronization and Management

Prostaglandin F2α (PGF2α) plays a central role in veterinary reproductive by inducing luteolysis, enabling synchronization in species such as and mares to facilitate fixed-time (AI). Its luteolytic effects were first demonstrated in in 1971, leading to FDA approval of dinoprost tromethamine (Lutalyse) in 1979 for double-injection protocols and 1981 for single injections. This allows producers to align breeding with AI, reducing labor for estrus detection and improving genetic dissemination. relies on regressing a functional (CL), dropping progesterone levels within 24 hours and triggering . In , efficacy exceeds 90% for luteolysis and subsequent estrus induction in cycling animals with a CL aged over 5 days post-ovulation; younger CLs are refractory. A standard single dose of 25 mg dinoprost tromethamine administered intramuscularly () causes estrus in 2-5 days, supporting protocols like LAIE (Lutalyse-AI at estrus). For broader herd synchrony, double injections 11-14 days apart (e.g., LLAIE) achieve pregnancy rates of 34-38% to AI at fixed times, outperforming unsynchronized controls (11%). These methods, refined since the , are most effective in postpartum or mature cycling females, excluding anestrus or prepubertal animals.
SpeciesTypical Dose (dinoprost)AdministrationKey Protocol Notes
Cattle25 mgIM, single or double (11-14 days apart)>90% efficacy if CL >5 days old; estrus 2-5 days post-injection
Mares5-10 mgIM, often doubleLuteolysis in CL >5 days; combined with progestogens for ovulation sync; estrus 3-7 days post
In mares, PGF2α dosing at 5-10 mg induces reliable luteolysis in CL beyond 5 days post-, with protocols often incorporating progestogens (e.g., 10-14 days) followed by PGF2α withdrawal to synchronize ovulation for timed AI. Double doses enhance efficacy and minimize side effects, yielding estrus 3-7 days after treatment in cycling individuals. These strategies, adapted from early research, support efficient breeding in equine operations by concentrating foaling dates and optimizing use.

Uterine Infection and Pyometra Treatment

Prostaglandin F2α (PGF2α), administered as dinoprost or its tromethamine salt, serves as a key agent in the medical treatment of in dogs and cats, as well as and in , by promoting the evacuation of uterine contents. In these conditions, characterized by bacterial overgrowth and accumulation under progesterone influence from a persistent , PGF2α induces luteolysis, rapidly decreasing serum progesterone concentrations. This hormonal shift relaxes the uterine environment, enabling strong myometrial contractions that expel purulent and facilitate endometrial recovery. Treatment protocols typically combine PGF2α with systemic antibiotics, such as amoxicillin-clavulanate or , to combat pathogens like . For bitches, low-dose regimens begin at 10 µg/kg subcutaneously 3–5 times daily on day 1, increasing to 25–50 µg/kg on subsequent days until vaginal discharge ceases and the animal returns to estrus, often over 5–7 days. Similar dosing applies to queens, adjusted for body weight, while in , single or repeated doses of 25 mg dinoprost tromethamine target postpartum uterine infections. This approach is preferred for breeding animals where ovariohysterectomy is undesirable. Clinical resolution, defined as restoration of health without , reaches 75–90% in open-cervix cases in dogs, with expulsion observed within 24–48 hours post-luteolysis. In endometritis, PGF2α enhances uterine clearance rates to 80% or higher when integrated with . However, success diminishes in closed-cervix due to obstructed drainage, and recurrence occurs in 40–48% of treated bitches within one year, underscoring the need for monitoring and potential repeat cycles.

Side Effects and Safety Considerations

Adverse Reactions in Humans

Prostaglandin F2α (PGF2α), administered as dinoprost tromethamine for therapeutic or , commonly induces gastrointestinal adverse reactions due to its stimulation of contraction. and occur in approximately 50% of patients, while affects a lesser but still significant proportion, often dose-related and manageable with . In clinical series for mid-trimester , rates reached 70%, with and fever (≥38°C) in 13.6% of cases. These effects arise from PGF2α's action on intestinal receptors, typically resolving post-treatment but contributing to patient discomfort during infusion protocols. Bronchoconstriction represents a serious respiratory , particularly in patients with or , where PGF2α inhalation or systemic exposure provokes airway narrowing via FP receptor activation on bronchial . This contraindicates its use in asthmatics, as evidenced by clinical guidelines and observed exacerbations in susceptible individuals. Cardiovascular effects include transient changes in and , potentially involving , though infusion studies show variable impacts without consistent in normotensive subjects. Off-target systemic exposure limits application in those with preexisting cardiovascular conditions. In abortifacient applications, PGF2α carries risks of incomplete expulsion, with failure to abort within 48 hours occurring in up to 42.6% of complicated cases, often necessitating surgical intervention like curettage alongside hematocrit drops >5% from bleeding. Uterine pain and fever are dose-dependent, stemming from myometrial hyperactivity, with temperatures ≥38°C in 10-14% of intra-amniotic administrations. Long-term reproductive outcome data remain limited, with no large-scale studies confirming persistent fertility impacts beyond acute complications.

Risks and Limitations in Veterinary Contexts

In veterinary applications, prostaglandin F2α (PGF2α, dinoprost tromethamine) administration commonly elicits transient systemic effects in responsive animals, including mild sweating, increased salivation, restlessness, and abdominal discomfort shortly after injection, typically resolving within hours. These reactions stem from its potent luteolytic and smooth muscle-contracting properties, with slight elevations in and rectal temperature (up to 1.5°F) observed in for up to 6 hours post-dose. Species-specific variations include and in dogs, often accompanied by panting and trembling during termination protocols, and severe in horses, which may necessitate supportive care due to heightened gastrointestinal sensitivity. Rare but serious adverse events encompass anaphylactic reactions, manifesting as , swelling, or respiratory distress, though incidence remains low in field reports across species. Injection-site complications, such as severe localized clostridial infections, occur infrequently but can be fatal in without prompt intervention, underscoring the need for aseptic administration. Additionally, increased , defecation frequency, , and nervousness reflect broader autonomic , with intensity modulated by dose, route, and animal condition. Limitations arise primarily from physiological dependencies: PGF2α induces luteolysis only in mature (typically >5 days post-ovulation), failing in anestrus animals lacking a functional or in those with young, refractory structures during early luteal phases, as demonstrated in bovine field trials where pre-day-5 corpora resisted regression despite varied dosing. Contraindications include use in pregnant animals intended for term delivery, as it reliably precipitates (e.g., ~93% efficacy up to 100 days in at 25 mg doses), and in individuals with pre-existing acute or subacute respiratory, gastrointestinal, or vascular disorders, where exacerbated contractions could precipitate crisis. Poor outcomes also correlate with underlying health deficits, such as or concurrent progestin exposure, reducing luteolytic response in herd studies. In mares, post- treatment in anestrous states may fail to restore cyclicity if functional endometrial cups persist beyond 36 days .

Synthesis and Production Methods

Laboratory and Organic Synthesis

The first total laboratory synthesis of prostaglandin F₂α (PGF₂α) was reported by Elias J. Corey in 1969, employing a 17-step linear sequence from simple precursors to construct the core and side chains. Central transformations included an mediated by dimsyl sodium in DMSO, proceeding in 80% yield over three steps to form key carbon-carbon bonds in the ring system. The ω-side chain was installed via Wittig olefination using NaH in DME, affording 70% yield over two steps while establishing the requisite cis double bond geometry. Stereoselective steps proved challenging due to the five chiral centers, particularly in the side chains; a Zn(BH₄)₂ reduction targeted the C15 hydroxyl group but delivered only 49% of the natural epimer alongside an equal amount of the C15-, necessitating separation and highlighting limitations in early asymmetric control. Additional encompassed mCPBA epoxidation (95% yield) for regioselective functionalization and selective reductions like i-Bu₂AlH at low temperature, though overall yields remained modest owing to PGF₂α's instability toward bases, oxidants, and purification stresses, impeding efficient laboratory scaling. Modern laboratory routes leverage chemoenzymatic strategies to enhance and brevity; a 2024 method synthesizes PGF₂α in five steps from commercial , initiating with enzymatic Baeyer-Villiger oxidation to yield a chiral intermediate and lipase-catalyzed desymmetrization for enantiopure mono-acetate formation. Chemical steps follow, including bromohydrin formation, nickel-catalyzed reductive coupling for the α-, and Wittig olefination for the cis-unsaturated ω-chain, culminating in gram-scale production (10.6 g from 14.2 g precursor) without noble metals and with improved stereocontrol via biocatalysts. These approaches address historical stereochemical hurdles by integrating enzymatic reductions and oxidations, reducing step count while maintaining high fidelity in assembly.

Industrial-Scale Production

Industrial-scale production of prostaglandin F2α (dinoprost) historically relied on semisynthetic methods using precursors extracted from the gorgonian Plexaura homomalla, harvested from reefs. The Upjohn Company adapted this approach in the early 1970s, processing coral yields of 2-3% prostaglandins—primarily PGA2 and PGB2—through base-catalyzed isomerization to PGE2, followed by selective reduction to PGF2α, achieving commercial viability for dinoprost tromethamine under the brand Prostin F2 Alpha. This extraction-dependent process supported initial pharmaceutical demands but faced sustainability challenges due to overharvesting, prompting shifts to synthetic routes. Modern manufacturing employs fully chemical synthetic processes to enhance efficiency and independence from natural sources, often starting from mimics or lactone intermediates via multi-step asymmetric synthesis involving Wittig reactions, aldol condensations, and stereoselective reductions. Yields improved significantly after the 1970s through optimized and , with overall conversions exceeding 20-30% in scaled operations. Purification to pharmaceutical grade (>99% purity) utilizes preparative , including normal-phase columns and reverse-phase HPLC, followed by of the tromethamine salt for improved and stability. Production adheres to Good Manufacturing Practices (GMP), with dinoprost tromethamine synthesized in certified facilities by manufacturers such as CentreOne and Euroapi, ensuring compliance with FDA and EMA standards for sterility, potency, and impurity limits below 0.1%. These processes prioritize cost-effectiveness for veterinary applications while maintaining high purity for human uses, avoiding microbial fermentation due to limitations in current commercial contexts.

Analogues and Derivatives

Key Synthetic Analogues

, chemically (15S)-15-methylprosta-5,9,13-trien-1-ol-7,11,15-triol with a tromethamine salt, incorporates a methyl at the C-15 position of PGF2α, which sterically hinders 15-hydroxyprostaglandin dehydrogenase-mediated and thereby extends its biological duration. This structural modification augments its oxytocic activity, enabling effective control of refractory postpartum hemorrhage from unresponsive to conventional therapies like oxytocin. Latanoprost represents a selectively modified PGF2α derivative, featuring saturation of the 13-14 , truncation of the omega chain to a at C-17, and an isopropyl ester moiety at the carboxyl terminus (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α isopropyl ester). These alterations improve corneal penetration and to the active free acid in ocular tissues, facilitating sustained reduction of via enhanced uveoscleral outflow in management. Bimatoprost, another ocular analogue, substitutes the carboxylic acid with an ethyl amide group (forming a prostamide) while retaining similar chain modifications, which boosts and receptor agonism for hypotensive effects and ancillary uses like eyelash hypotrichosis treatment. Cloprostenol, a veterinary-specific analogue, includes a atom at the C-16 position and omega chain truncation (16-chloro-17,18,19,20-tetranor-PGF2α), yielding heightened resistance to pulmonary inactivation and superior luteolytic efficacy over native PGF2α. This enables precise applications in livestock reproduction, including estrus synchronization protocols, resolution, and controlled parturition induction in , , and swine.

Pharmacological Modifications and Efficacy

Structural modifications to prostaglandin F2α (PGF2α), particularly at the 15-position through , confer resistance to enzymatic inactivation by 15-hydroxyprostaglandin , a primary that rapidly deactivates the native molecule. This alteration inhibits oxidation at the 15-hydroxyl group, extending the and duration of receptor engagement, which enhances overall pharmacological efficacy in applications requiring sustained activity, such as luteolysis or contraction. Structure-activity relationship (SAR) analyses demonstrate that targeted changes, including substitutions in the omega-chain or introduction of aromatic rings like phenyl groups, can modulate binding affinity to the FP receptor. Certain phenyl-substituted analogues exhibit binding potencies equal to or exceeding that of native PGF2α, with relative affinities often quantified through competitive displacement assays showing values in the low nanomolar range comparable to or better than the endogenous ligand's Ki of approximately 1-10 nM. These modifications typically preserve or amplify FP receptor activation while altering transporter interactions, reducing rapid clearance and improving tissue-specific delivery. In glaucoma management, such display superior efficacy to native PGF2α owing to heightened FP receptor selectivity and optimized , including esterification for enhanced corneal penetration and reduced systemic exposure. Clinical potency ratios indicate that analogues like those with isopropyl esters achieve reductions of 25-35% with once-daily dosing, surpassing the short-lived effects of unmodified PGF2α, which exhibits non-specific binding and lower therapeutic indices due to with other receptors. This selectivity minimizes off-target effects, such as bronchial constriction, while maintaining equipotent or greater agonism at the FP receptor ( values often <1 nM versus 10 nM for PGF2α).

Recent Research Developments

Receptor Structure and Signaling Insights

In 2023, cryo-electron microscopy (cryo-EM) structures of the human prostaglandin F2α receptor (FP receptor, PTGFR) provided atomic-level resolution of its orthosteric binding pocket and activation mechanisms. Structures bound to the endogenous ligand PGF2α, latanoprost free acid (LTPA), and tafluprost free acid (TFPA) were resolved at 2.67 Å, 2.78 Å, and 3.14 Å, respectively, revealing ligand-induced conformational changes that facilitate Gq coupling. Additional structures with carboprost and LTPA at 2.7 Å and 3.2 Å highlighted determinants of ligand and G protein selectivity. The orthosteric pocket divides into three sub-pockets accommodating PGF2α's α-chain (via polar interactions including a salt bridge with Arg2917.40 and hydrogen bonds with Tyr922.65 and Thr184ECL2), ω-chain (hydrophobic enclosure by Met1153.32, Phe1874.55, Phe2055.41, Trp2626.48, and Phe2656.51), and F-ring (hydrogen bonds from Ser331.39, His812.54, and Thr2947.43 to the 9α- and 11α-hydroxyls). The Trp2626.48 residue acts as a toggle switch, displacing upon binding to form an LLW triad (Leu1233.40-Leu2135.49-Trp2626.48) that stabilizes the active state; its compact positioning enhances affinity for PGF2α's C15-20 ω-chain while excluding bulkier PGE2 variants. F-ring interactions confer selectivity over EP receptors, as the 11α-hydroxyl enables unique hydrogen bonding absent in PGE2's group. For synthetic analogs like latanoprost-FA, Phe2656.51 mediates π-π stacking with the ring, explaining isoform-specific potency in therapeutics. Ligand engagement induces transmembrane (TM) rearrangements, including TM6 outward displacement by 6.7 and TM7 inward shift, opening a cavity for Gαq engagement without reliance on a PIF motif. Gq selectivity arises from receptor residues Arg571.49, His1433.53, and His2446.30 forming polar contacts with the Gαq α5 , coupled with a modest TM6 shift relative to Gs- or Gi-coupled GPCRs, which optimizes C-β activation. This pathway drives inositol 1,4,5-trisphosphate generation and intracellular calcium release, underpinning FP-mediated contractions in reproductive and ocular tissues. These insights enable rational by targeting sub-pocket-specific modifications; for instance, enhancing F-ring interactions could yield selective agonists minimizing with EP or DP receptors, while Gq-interface mutations might decouple for safer luteolytics or abortifacients.

Novel Applications and Ongoing Studies

Recent investigations have elucidated the role of F2α (PGF2α) in exacerbating dry eye disease through promotion of fibrosis. A 2025 study using mouse models demonstrated that PGF2α administration intensified fibrosis progression via activation of the RhoA/ROCK signaling pathway, leading to increased expression of fibrotic markers such as α-smooth muscle and I. This pathway inhibition, alongside PGF2α blockade, reduced fibrotic changes and improved tear production, suggesting potential therapeutic targets for fibrosis-driven ocular surface disorders. The isoprostane 8-iso-PGF2α, a of closely linked to PGF2α biosynthetic pathways, has emerged as a urinary indicator of type 2-low airway in severe . In a 2024 cohort analysis of adults with , elevated urinary 8-iso-PGF2α levels correlated with noneosinophilic phenotypes, reflecting heightened and airway remodeling independent of eosinophilic . These findings position 8-iso-PGF2α as a non-invasive tool for phenotyping subtypes refractory to type 2-targeted biologics, with levels distinguishing T2-low from T2-high disease. In myometrial contexts, PGF2α drives through calcium-dependent mechanisms, as evidenced by 2023 experiments on primary myometrial cells from term pregnancies. Exposure to PGF2α elevated and MAP kinase activation, upregulating COX-2 and pro-inflammatory cytokines, thereby linking it to parturition-associated inflammatory cascades. This pro-inflammatory action persists despite PGF2α's primary contractile effects, highlighting a mechanistic overlap in without resolving broader paradoxes observed in select non-reproductive tissues. Ongoing preclinical trials target these pathways to modulate preterm labor risks, though translation remains exploratory.

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