Norgestrel
Übersicht
Beschreibung
Levonorgestrel is a synthetic steroidal progestin used primarily in combination with ethinyl estradiol for oral contraception. It is composed of a racemic mixture of two stereoisomers: dextrothis compound and levothis compound. only the levorotary enantiomer (levothis compound) is biologically active . Levothis compound is also used in menopausal hormone therapy and is available as a generic medication .
Wirkmechanismus
Target of Action
Norgestrel, specifically its biologically active stereoisomer levothis compound, primarily targets the progesterone and estrogen receptors within the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary . These receptors play crucial roles in the regulation of the menstrual cycle and pregnancy.
Mode of Action
This compound binds to the progesterone and estrogen receptors, leading to a series of changes in the reproductive system. Once bound to the receptor, progestins like levothis compound slow the frequency of release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory luteinizing hormone (LH) surge . This loss of the LH surge inhibits ovulation, thereby preventing pregnancy .
Biochemical Pathways
The binding of this compound to progesterone and estrogen receptors affects several biochemical pathways. It suppresses ovulation in approximately half of users, thickens the cervical mucus to inhibit sperm penetration , and triggers changes in the endometrium . Additionally, it has been found to enhance oxidative phosphorylation via the wingless/integrated signaling pathway and trigger reactive oxygen species (ROS) generation .
Pharmacokinetics
This compound is rapidly and completely absorbed, with maximum concentrations reached 1.0 – 2.0 hours after ingestion . The elimination of this compound has two phases with half-lives of 0.5 and 20 – 60 hours . These properties influence the bioavailability of this compound and its effectiveness as a contraceptive.
Result of Action
The primary result of this compound’s action is the prevention of pregnancy. It achieves this by stopping a woman’s egg from fully developing each month . The egg can no longer accept a sperm, and fertilization is prevented . This compound also causes changes in the endometrium and cervical mucus, further preventing the possibility of pregnancy .
Action Environment
The action, efficacy, and stability of this compound can be influenced by various environmental factors. For instance, certain drugs can interact with this compound and affect its contraceptive efficacy. Drugs such as apalutamide and carbamazepine, which affect hepatic/intestinal enzyme CYP3A4 metabolism, can decrease the serum concentration of this compound, potentially leading to contraceptive failure . Therefore, it’s recommended for patients to use an alternative method of contraception or a back-up method during coadministration of these drugs .
Wissenschaftliche Forschungsanwendungen
Levonorgestrel has a wide range of scientific research applications, including:
Chemistry
In chemistry, this compound is studied for its synthetic pathways and chemical properties. Researchers explore new methods for its synthesis and modification to improve its efficacy and reduce side effects.
Biology
In biology, this compound is used to study hormone regulation and reproductive biology. It serves as a model compound to understand the effects of progestins on cellular processes.
Medicine
In medicine, this compound is extensively used in contraceptive pills and hormone replacement therapy. It is also being investigated for its potential neuroprotective effects in retinal diseases .
Industry
In the pharmaceutical industry, this compound is a key ingredient in various contraceptive formulations. Its production and quality control are critical for ensuring the safety and efficacy of these products.
Biochemische Analyse
Biochemical Properties
Norgestrel interacts with various enzymes and proteins in biochemical reactions. It exerts its contraceptive action by several mechanisms: reduction in the sperm penetrability of the cervical mucus and an impairment of luteal function appear important . The serum concentrations of cholesterol and globulin were significantly reduced in women taking this compound .
Cellular Effects
This compound has significant effects on various types of cells and cellular processes. It influences cell function, including impact on cell signaling pathways, gene expression, and cellular metabolism .
Molecular Mechanism
This compound exerts its effects at the molecular level, including binding interactions with biomolecules, enzyme inhibition or activation, and changes in gene expression .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound change over time. This includes information on the product’s stability, degradation, and any long-term effects on cellular function observed in in vitro or in vivo studies .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models . This includes any threshold effects observed in these studies, as well as any toxic or adverse effects at high doses .
Metabolic Pathways
This compound is involved in various metabolic pathways, including interactions with enzymes or cofactors . This also includes any effects on metabolic flux or metabolite levels .
Transport and Distribution
This compound is transported and distributed within cells and tissues . This includes any transporters or binding proteins that it interacts with, as well as any effects on its localization or accumulation .
Subcellular Localization
This could include any targeting signals or post-translational modifications that direct it to specific compartments or organelles .
Vorbereitungsmethoden
Synthetic Routes and Reaction Conditions
Levonorgestrel is synthesized through a series of chemical reactions starting from steroidal precursors. The synthesis involves multiple steps, including oxidation, reduction, and substitution reactions. The specific details of the synthetic routes and reaction conditions are proprietary to the manufacturers and are not publicly disclosed in detail.
Industrial Production Methods
Industrial production of this compound involves large-scale chemical synthesis using advanced techniques to ensure high purity and yield. The process is optimized for cost-effectiveness and efficiency, adhering to stringent quality control measures to meet regulatory standards.
Analyse Chemischer Reaktionen
Types of Reactions
Levonorgestrel undergoes various chemical reactions, including:
Oxidation: Conversion of hydroxyl groups to ketones.
Reduction: Reduction of ketones to hydroxyl groups.
Substitution: Replacement of functional groups with other substituents.
Common Reagents and Conditions
Common reagents used in these reactions include:
Oxidizing agents: Such as chromium trioxide and pyridinium chlorochromate.
Reducing agents: Such as lithium aluminum hydride and sodium borohydride.
Substitution reagents: Such as alkyl halides and organometallic compounds.
Major Products
The major products formed from these reactions include various intermediates that are further processed to yield the final this compound compound.
Vergleich Mit ähnlichen Verbindungen
Similar Compounds
Norethindrone: Another synthetic progestin used in oral contraceptives and hormone therapy.
Levonorgestrel: The biologically active enantiomer of this compound, used in emergency contraception and intrauterine devices.
Uniqueness
Levothis compound is unique due to its racemic mixture composition, which includes both dextrothis compound and levothis compound. This composition allows for a broader range of applications and effects compared to other progestins that may only contain a single stereoisomer.
Eigenschaften
CAS-Nummer |
6533-00-2 |
|---|---|
Molekularformel |
C21H28O2 |
Molekulargewicht |
318.5 g/mol |
IUPAC-Name |
(10R,13S,17R)-2,2,4,6,6,10-hexadeuterio-13-ethyl-17-ethynyl-17-hydroxy-7,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3-one |
InChI |
InChI=1S/C21H28O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,13,16-19,23H,3,5-12H2,1H3/t16-,17?,18?,19?,20-,21-/m0/s1/i5D2,6D2,13D,16D |
InChI-Schlüssel |
WWYNJERNGUHSAO-PHHWYCLISA-N |
Verunreinigungen |
Reported impurities include: 13-ethyl-3,4-diethynyl-18,19-dinor-17alpha-pregn-5-en-20- yn-3beta,4alpha,17-triol, 13-ethyl-3,4-diethynyl-18,19-dinor-17alpha-pregn-5-en-20-yn-3alpha,4alpha,17- triol 13-ethyl-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol, 13-ethyl-3-ethynyl-18,19-dinor-17alpha-pregna-3,5-dien-20-yn-17-ol, 13-ethyl-17-hydroxy-18,19-dinor-17alpha-pregna-4,8(14)- dien-20-yn-3-one and 13-ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-5(10)-en-20-yn-3-one. |
SMILES |
CCC12CCC3C(C1CCC2(C#C)O)CCC4=CC(=O)CCC34 |
Isomerische SMILES |
[2H]C1=C2[C@](CC(C1=O)([2H])[2H])(C3CC[C@]4(C(C3CC2([2H])[2H])CC[C@]4(C#C)O)CC)[2H] |
Kanonische SMILES |
CCC12CCC3C(C1CCC2(C#C)O)CCC4=CC(=O)CCC34 |
Aussehen |
Solid powder |
Siedepunkt |
459.1 |
Color/Form |
Crystals from methanol Crystals from diethyl ether-hexane |
melting_point |
205-207 °C |
| 6533-00-2 797-63-7 |
|
Physikalische Beschreibung |
Solid |
Piktogramme |
Health Hazard; Environmental Hazard |
Reinheit |
>98% (or refer to the Certificate of Analysis) |
Haltbarkeit |
>2 years if stored properly |
Löslichkeit |
In water, 1.73 mg/L, temp not stated. |
Lagerung |
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
Synonyme |
18,19-dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17alpha)-(-)- Capronor Cerazet D Norgestrel D-Norgestrel duofem l Norgestrel l-Norgestrel Levonorgestrel Microlut Microval Mirena Norgeston NorLevo Norplant Norplant 2 Norplant-2 Norplant2 Plan B Vikela |
Dampfdruck |
1.0X10-9 mm Hg at 25 °C (est) 3.92X10-10 mm Hg at 25 °C (est) |
Herkunft des Produkts |
United States |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: How does Norgestrel exert its contraceptive effects?
A1: this compound, specifically its biologically active enantiomer Levothis compound, primarily exerts its contraceptive effects through multiple mechanisms. It acts by []:
Q2: What is the role of basic fibroblast growth factor (bFGF) in this compound's neuroprotective effects?
A2: Research suggests that this compound's neuroprotective properties may involve the upregulation of bFGF. Studies on photoreceptor cells and retinal explants demonstrated that this compound increased bFGF expression []. Furthermore, inhibiting bFGF with specific siRNA blocked this compound's protective effects in stressed photoreceptors, highlighting bFGF's crucial role in this process [].
Q3: Does this compound impact microglia activity in the retina?
A3: Yes, studies show that this compound administration in a mouse model of retinitis pigmentosa (RP) led to alterations in microglial activity coinciding with significant retinal protection []. This suggests that changes in microglial behavior may contribute to this compound's neuroprotective effects.
Q4: How does this compound affect gliosis in the retina?
A4: this compound has been shown to reduce gliosis, a characteristic feature of retinal degeneration. In the rd10 mouse model of RP, this compound treatment resulted in decreased microglial activity and a reduction in Müller cell gliosis, marked by decreased glial fibrillary acidic protein (GFAP) expression [].
Q5: What role do reactive oxygen species (ROS) play in this compound-mediated retinal neuroprotection?
A5: While often associated with cellular damage, research suggests that this compound utilizes a controlled burst of pro-survival ROS downstream of bFGF signaling to promote photoreceptor survival. This was observed in both photoreceptor-like cells and the rd10 mouse model [].
Q6: What is the molecular formula and weight of this compound?
A6: this compound has a molecular formula of C21H28O2 and a molecular weight of 312.45 g/mol.
Q7: How does the structure of this compound relate to its biological activity?
A7: this compound exists as two enantiomers, only one of which is biologically active. The active enantiomer, Levothis compound, possesses all the hormonal activity [, ]. Studies comparing the two enantiomers in various biological assays confirmed the inactivity of the dextrorotatory enantiomer and showed that Levothis compound was twice as potent as the racemic this compound in relevant experiments [].
Q8: How is this compound formulated for different delivery methods?
A8: this compound has been incorporated into various delivery systems, including:
- Oral contraceptives: this compound is commonly formulated with ethinyl estradiol in combined oral contraceptive pills [, , , , , , , ].
- Intrauterine devices (IUDs): this compound-releasing IUDs provide localized and long-acting contraceptive effects [, , ].
- Subcutaneous implants: Silastic implants containing Levothis compound crystals allow for prolonged diffusion and contraceptive action [].
- Vaginal rings: Rings releasing this compound and ethinyl estradiol provide continuous hormone delivery for several weeks [].
- Transdermal delivery: Research explores protransfersomes as potential carriers for enhanced this compound delivery through the skin [].
Q9: What are some alternative progestins used in contraceptive formulations?
A9: Several other progestins are used in contraceptive formulations, including:
- Norethisterone: A common progestin often used in combination with ethinyl estradiol [, , , , , , ].
- Lynestrenol: Another progestin used in oral contraceptives [, , , ].
- Desogestrel: A third-generation progestin known for its high progestational activity [].
- Medroxyprogesterone acetate: Used in injectable contraceptives and some combined oral contraceptives [, , ].
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