Cabergoline powder, also known as Dostinex (R), is a white to off white powdery substance. The melting point is between 102 and 104 ℃. It is also a dopamine receptor agonist with strong, long-lasting, and selective characteristics. It has a high affinity for D2 dopamine receptors and works by stimulating D2 dopamine receptors, thereby inhibiting the secretion of prolactin by the anterior pituitary gland and reducing prolactin levels in the blood. It is mainly used to treat disorders related to hyperprolactinemia, as well as to manage symptoms of Parkinson's syndrome. It can be used as a monotherapy for early symptom management or as an adjuvant medication for levodopa treatment in late stages of the disease.
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Chemical Formula |
C26H37N5O2 |
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Exact Mass |
451.29 |
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Molecular Weight |
451.62 |
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m/z |
451.29(100.0%),452.30(28.1%),453.30(2.7%),452.29(1.8%),453.30(1.1%) |
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Elemental Analysis |
C,69.15;H,8.26:N,15.51;O,7.09 |
It is insoluble in water, soluble in ethanol or chloroform, and has hygroscopicity. It should be stored at 2-8 ℃ to avoid contact with strong oxidants, strong bases, strong reducing agents, and strong acids that may cause it to deteriorate.
Cabergoline is a derivative of ergot alkaloids, which acts as a long-acting dopamine receptor agonist. Its core mechanism of action is to selectively excite dopamine D2 receptors, inhibit prolactin secretion in the anterior pituitary gland, and have a weak excitatory effect on D1 receptors.
Human medical field: multi-target therapy from endocrine to nervous system
1. Hyperprolactinemia and related diseases
Core indications:
Cabergoline powder is the preferred drug for treating hyperprolactinemia, especially for patients with pituitary prolactinoma. It significantly reduces serum prolactin levels by continuously stimulating D2 receptors, inhibiting prolactin secretion for up to two weeks. Clinical data shows that treatment can restore normal prolactin levels in 83% of patients and restore ovulation cycles in 72%, which is much better than the traditional drug bromocriptine (52% and 58%). For patients with prolactinoma, cabergoline not only controls hormone secretion but also reduces tumor volume and pressure on surrounding tissues.
Symptom relief and reproductive function recovery:
Hyperprolactinemia often leads to menstrual disorders, amenorrhea, galactorrhea, and infertility in women, while men experience decreased libido, breast development, and infertility. By reducing prolactin levels, it is possible to effectively alleviate symptoms such as breast tenderness and galactorrhea, and restore menstrual cycle and reproductive function. For example, in the study conducted at the First Hospital of Shijiazhuang City, the decrease in serum prolactin levels of patients treated with cabergoline at 1, 3, and 6 months after treatment was significantly higher than that of patients treated with bromocriptine, and the success rate of pregnancy was higher.
Long term health management:
Long term hyperprolactinemia may inhibit hormone secretion and lead to osteoporosis. Adjusting hormone levels can help prevent osteoporosis and improve long-term prognosis for patients. During the treatment period, regular monitoring of prolactin levels and changes in pituitary adenomas is required, usually with imaging examinations conducted every 2-3 years. Asymptomatic patients may have extended follow-up intervals.
2. Parkinson's disease and movement disorders
Single drug therapy and combination therapy:
Used for the treatment of Parkinson's Disease, it can be used as a monotherapy or in combination with levodopa. It enhances the dopaminergic effect of the central nervous system, reduces the dosage and fluctuation of levodopa (such as the "end of dose phenomenon" and "on/off" state).
Research has shown that combined treatment with levodopa can significantly reduce the demand for levodopa by 18%, prolong the "on" state time, and improve patients' daily living ability and exercise scores.
Early intervention and advanced treatment:
Some neurologists use it for early treatment of Parkinson's disease to delay the use of levodopa.
Others use it as an alternative when levodopa becomes ineffective or intolerant. Its long-lasting properties (half-life of about 6 hours) and low-dose requirements (usually twice a week) improve patient compliance, making it particularly suitable for elderly patients.
Improvement of motor symptoms:
It can alleviate the core symptoms of Parkinson's disease, such as tremors, stiffness, and bradykinesia. It enhances the function of the nigrostriatal pathway and improves motor control by stimulating dopamine receptors.
Clinical observations have shown that patients' exercise flexibility is significantly improved after medication, and their daily living abilities (such as dressing and eating) are improved.
3. Adjuvant treatment of breast cancer
Potential mechanism of action:
The activation of cabergoline powder on dopamine receptor may inhibit the growth of some breast cancer cells and promote their apoptosis. Although the evidence is not sufficient at present, the experimental application shows that it has a certain effect on some hormone receptor positive breast cancer patients, which may play a role by regulating prolactin related signal pathways.
Current clinical application status:
In the treatment of breast cancer, it is still in the exploratory stage, and the indications should be strictly controlled. Usually used for adjuvant therapy, it needs to be combined with other therapies (such as surgery, chemotherapy) under the guidance of professional physicians, and closely monitored for efficacy and adverse reactions.
4. Other potential uses
Return of milk and lactation inhibition
Can be used for milk return, but not recommended for routine use to inhibit physiological lactation. It reduces milk production by inhibiting prolactin secretion, but attention should be paid to dosage control (usually no more than 1mg per dose) to avoid excessive inhibition leading to breast atrophy or hormonal imbalance.
Mental and neural regulation
Some studies suggest that it may have an adjuvant therapeutic effect on mental and neurological disorders such as neurasthenia and anxiety disorders, but its mechanism is still unclear and needs further verification. At present, clinical applications are still mainly focused on endocrine and neurological diseases.
Animal Medicine: Reproductive Management and Termination of Pregnancy
1. Dog breeding management
Inducing/synchronizing estrus:
Can be used for inducing and synchronizing estrus in dogs, promoting follicular development and ovulation by regulating the hypothalamic pituitary gonadal axis function. The typical usage is oral administration of 5 μ g/kg once a day for 4-25 days, which can significantly improve the estrus rate and facilitate centralized breeding.
Pseudopregnancy therapy:
For False Pregnancy dogs, inhibiting prolactin secretion can alleviate breast swelling, lactation, and behavioral abnormalities such as nesting and protecting offspring. The usage is oral administration of 5 μ g/kg once a day for 5-10 consecutive days. For severe symptoms, subcutaneous injection can be administered in combination with other medications.
2. Termination of pregnancy and abortion
Dog and cat abortion
Can be used as an abortion drug for dogs or cats, by inhibiting corpus luteum function and promoting embryonic arrest. After 30 days of mating, oral administration of 5 μ g/kg, once every 24 hours, combined with clopidogrel (5 μ g/kg, subcutaneous injection, once every 48 hours) can improve the success rate of miscarriage.
Postpartum lactation suppression
Postpartum use of cabergoline powder can inhibit breast secretion, but close monitoring of blood pressure changes is necessary to avoid the risk of hypotension. It is recommended to take medication at least 4 hours after delivery and after stable vital signs. The dosage should be adjusted according to individual needs.
Medication guidance
When taking medication, it is necessary to follow the doctor's advice and guidance, strictly control the dosage and course of treatment. For specific populations, such as pregnant women, breastfeeding women, and children, caution should be exercised when using and relevant medication guidelines should be followed.
Drug storage
Store in a suitable temperature environment, it is recommended to store at a temperature of 20 ℃~25 ℃ to avoid exposing the drug to too high or too low, which may reduce its stability and efficacy.
Drug interactions
Dopamine antagonists such as metoclopramide or phenothiazine can reduce their effectiveness and should be avoided for simultaneous use. They also have a blood pressure lowering effect, but if used together with other antihypertensive drugs, it may lead to an additive effect in lowering blood pressure.
Parkinson's treatment needs
With the advancement of diagnostic technology for prolactinoma, the demand for drugs that can effectively control prolactin levels will continue to increase. As an effective drug for treating prolactinoma, its market demand will also grow accordingly.
Treatment needs for prolactinoma
Parkinson's disease is a chronic neurodegenerative disease for which there is currently no cure. It can improve the motor function and quality of life of Parkinson's disease patients by stimulating dopamine receptors, so its market prospects are broad.
Other indications and requirements
In addition to prolactinoma and Parkinson's disease, it is also being studied for the treatment of other diseases such as infertility and breast lesions. These new indications will further expand the market space.
The prevailing synthetic processes for cabergoline powder are divided into classic laboratory routes and improved industrial routes, both centering on modification of the ergoline scaffold, construction of side chains, and precise transformation of functional groups.
Classic Synthetic Route
The classic synthetic route uses methyl 6-nordihydrolysergate as the starting material. Featuring straightforward procedures, it is suitable for small-scale laboratory preparation.
The first step involves N-alkylation at the 6-position: propargyl bromide undergoes nucleophilic substitution at the secondary amine at position 6 of the ergoline scaffold to yield the intermediate methyl 6-propargylergolinate. To prevent degradation of the indole ring, Pd/C is adopted as the hydrogenation catalyst with quinoline acting as a catalyst inhibitor. Under mild conditions, the alkyne is selectively reduced to afford the key 6-allyl-substituted intermediate, avoiding side reactions arising from excessive reduction of the double bond.
Subsequently, transamidation is carried out. The intermediate reacts with N,N-dimethyl-1,3-propanediamine under anhydrous inert conditions to form the core amide intermediate N-[3-(dimethylamino)propyl]-6-allylergoline-8β-carboxamide. Finally, addition reaction between this intermediate and ethyl isocyanate constructs the signature unsymmetrical acylurea moiety of the molecule.
Crude cabergoline is obtained after simple isolation. This route has obvious drawbacks: ethyl isocyanate exhibits high toxicity, and poor reaction selectivity readily leads to chiral isomers and bis-acylurea impurities, posing great separation difficulties. Hence, it fails to meet the requirements of industrial manufacturing.
Improved Industrial Synthetic Route
To address the deficiencies of the classic route, the dominant industrial approach replaces the isocyanate procedure with a two-step phenyl chloroformate-ethylamine method, substantially enhancing process safety and selectivity for scaled-up production. Using the aforementioned amide intermediate as the substrate, the process first reacts the substrate with phenyl chloroformate in a weakly alkaline low-temperature system to form a highly active phenyl carbamate intermediate, which achieves targeted activation of the designated amino site.
Low-temperature aminolysis with ethylamine then directionally builds the unsymmetrical acylurea framework, effectively suppressing epimerization of the parent scaffold induced by elevated temperatures.
High-end manufacturing processes incorporate a Boc protection–deprotection sequence. The reactive nitrogen on the indole ring is first protected with tert-butoxycarbonyl to block undesired side reactions.
Upon completion of acylurea construction, dilute hydrochloric acid is used to remove the protecting group at low temperature. This strategy markedly reduces impurity formation and improves the optical purity of the product. The only downside is the addition of two reaction steps, which moderately lowers the overall yield; optimized reaction parameters are required to strike a balance between purity and yield.
Control of Key Synthetic Process Challenges
Preservation of chiral configuration stands as the core challenge. The chiral center at the 8-position of ergoline has low stability and is prone to epimerization.
Accordingly, all reactions require strict temperature control, light exclusion, and anhydrous inert solvents, with continuous HPLC monitoring of isomer levels throughout the process.
Meanwhile, the 6-allyl side chain is sensitive to strong acids and strong oxidizing environments, which may trigger double bond migration and isomerization.
Hydrogen pressure and catalyst loading in hydrogenation must be precisely regulated. Furthermore, multiple reactive nitrogen atoms exist within the molecule. Controlling feed ratios and adopting a sequential activation strategy enables preferential reaction at the target site and inhibits byproduct generation.
Product Purification and Process Summary
Upon reaction completion, crude product is acquired via water washing, brine extraction and concentration of the organic phase. Silica gel column chromatography is employed for laboratory purification, whereas industrial production adopts toluene-n-heptane anti-solvent crystallization.
Multiple recrystallization cycles deliver high-purity active pharmaceutical ingredient (API). In overview, the classic route features simple operation yet suffers from abundant impurities and poor safety, and is only applicable to lab-scale trials.
The optimized two-step method operates under mild conditions with high selectivity and represents the dominant industrial technology at present. The protection-group-augmented optimized process enables production of ultra-high-purity products to satisfy high-end pharmaceutical manufacturing demands.
Physicochemical Properties
Cabergoline is a white to off-white crystalline powder at ambient temperature. It is practically insoluble in water, while readily soluble in organic solvents such as ethanol and dichloromethane. The molecule contains multiple chiral centres and exhibits optical isomerism; the pharmaceutical form corresponds to a single enantiomer. It is sensitive to light and oxygen, hence storage under light-proof and hermetically sealed conditions is required. It possesses a stable melting range, and its crystalline form directly impacts the dissolution performance of pharmaceutical formulations.
Pharmacological Characteristics
This product is a long-acting selective dopamine D₂ receptor agonist with negligible affinity for D₁ receptors. It features a prolonged half-life, and a single dose exerts therapeutic effects lasting for several days by persistently inhibiting pituitary prolactin secretion. Oral absorption is favourable, yet significant first-pass metabolism occurs, leading to interindividual variability in bioavailability.
Stability and Compatibility Profile
Optimal stability is achieved under neutral pH conditions. Hydrolysis of the acylurea linkage and epimerisation at the C-8 chiral centre readily take place under strongly acidic or strongly alkaline conditions. Coexistence with strong oxidising agents should be avoided. It is commonly formulated as tablets to prevent prolonged storage in aqueous solutions. Hepatic metabolism constitutes the primary elimination pathway, and only a small fraction of the parent drug is excreted via urine. Dose adjustment with caution is necessary for patients with hepatic impairment.
FAQ
What is the drug cabergoline used for?
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Cabergoline is used to treat different types of medical problems that occur when too much of the hormone prolactin is produced. It can be used to treat certain menstrual problems, fertility problems in men and women, and pituitary prolactinomas (tumors of the pituitary gland).
When is the best time to take cabergoline?
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Cabergoline is a long-acting medication, usually taken once or twice a week. Cabergoline can make you feel a bit dizzy, or cause nausea or headaches. Side-effects may be reduced if you take the cabergoline with food, or last thing at night before going to bed.
What is the mechanism of action of cabergoline?
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Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Results of in vitro studies demonstrate that cabergoline exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary lactotrophs. Cabergoline decreased serum prolactin levels in reserpinized rats.
What does cabergoline do for fertility?
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Because hyperprolactinaemia is a significant cause of infertility in women, cabergoline and other dopamine agonists are frequently prescribed to reduce prolactin levels and restore normal menses. They are usually discontinued shortly after the patient becomes pregnant.
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