Quinagolide

Identification

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Name
Quinagolide
Accession Number
DB09097
Type
Small Molecule
Groups
Approved, Investigational
Description

Quinagolide is a non-ergot-derived selective dopamine D2 receptor agonist used for the treatment of elevated levels of prolactin or hyperprolactinaemia. Hyperprolalctinaemia is associated with gonadal dysfunction, including infertility and reduced libido, as well as long-term complications such as osteoporosis 1. Newer dopamine receptor agonists such as quinagolide and Cabergoline are shown to effectively inhibit prolactin secretion with improved efficacy over Bromocriptine. These drugs are effective in patients who are intolerant or resistant to Bromocriptine. Quinagolide exists as a racemate and its relevant clinical activity is mediated predominantly by the (-) enantiomer. It is typically present in the hydrochloride salt form and is marketed as oral tablets under the brand name Norprolac contained as a racemate. Quinagolide is currently available in several countries including Canada, but not approved for treatment in the United States.

Structure
Thumb
Synonyms
  • (+-)-N,N-Diethyl-N'-((3R*,4aR*,10aS*)-1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-propylbenzo(g)quinolin-3-yl)sulfamide
  • Quinagolida
  • Quinagolide
  • Quinagolidum
Product Ingredients
IngredientUNIICASInChI Key
Quinagolide hydrochloride33474X943Y94424-50-7DVLKVIJLALMCBQ-VENMBWNLSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NorprolacTablet0.075 mgOralFerring Pharmaceuticals2004-12-29Not applicableCanada
NorprolacTablet0.05 mgOralFerring Pharmaceuticals2004-12-29Not applicableCanada
NorprolacTablet0.025 mgOralFerring Pharmaceuticals2004-12-29Not applicableCanada
NorprolacTablet0.15 mgOralFerring Pharmaceuticals2004-12-29Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
80Q9QWN15M
CAS number
87056-78-8
Weight
Average: 395.56
Monoisotopic: 395.224263109
Chemical Formula
C20H33N3O3S
InChI Key
GDFGTRDCCWFXTG-ZIFCJYIRSA-N
InChI
InChI=1S/C20H33N3O3S/c1-4-10-22-14-17(21-27(25,26)23(5-2)6-3)11-16-12-18-15(13-19(16)22)8-7-9-20(18)24/h7-9,16-17,19,21,24H,4-6,10-14H2,1-3H3/t16-,17+,19-/m1/s1
IUPAC Name
(3S,4aS,10aR)-3-[(diethylsulfamoyl)amino]-1-propyl-1H,2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinolin-6-ol
SMILES
[H][C@]12C[C@@H](CN(CCC)[C@]1([H])CC1=CC=CC(O)=C1C2)NS(=O)(=O)N(CC)CC

Pharmacology

Indication

Indicated for the treatment of hyperprolactinemia (idiopathic or originating from a prolactin-secreting pituitary microadenoma or macroadenoma).

Associated Conditions
Pharmacodynamics

Quinagolide achieves long-lasting reduction in prolactin levels in a dose-proportional effect via selectively targeting D2 receptors as an agonist. It potently suppresses both basal and stimulated serum prolactin levels by exerting a strong inhibitory effect on the secretion of the anterior pituitary hormone prolactin.

Mechanism of action

Prolactin secretion from the lactotroph cells present in the anterior pituiatry gland is under tonic inhibitory control mediated by dopaminergic signalling via D2 receptors 5. Quinagolide selectively binds to D2 receptors expressed on the surface of lactotroph cells with high affinity which results in reduced adenylyl cyclase activity, reduced intracellular cyclic adenosine monophosphate and inhibited prolactin secretion. It also binds to D1 receptors but with low affinity and little clinical relevance 1.

TargetActionsOrganism
UD(2) dopamine receptor
agonist
Humans
UD(1) dopamine receptor
agonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

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Absorption

The absorption of quinagolide is rapid and extensive with 95% of the dose absorbed after oral ingestion, however the absolute bioavailability is low (4 %) due to pre-systemic metabolism. The time to reach peak plasma concentration is 30-60 minutes. Prolactin-lowering effect of quinagolide at recommended therapeutic doses occurs within 2 hours after ingestion reaches a maximum within 4 to 6 hours and is maintained for at least 24 hours 7.

Volume of distribution

Approximate volume of distribution is 100L following a single oral admininstration. The parent drug and metabolites is predicted to be extensively distributed in the extravascular compartment with primary target organs being the liver, kidneys, salivary glands and pituitary Label.

Protein binding

Plasma protein binding is reported to be non-specific with an approximate ratio of 90%.

Metabolism

Quinagolide undergoes extensive first pass metabolism with sulfate and glucuronide conjugates being the major circulating metabolites. N-desethyl analogue is a biologically active metabolite while sulfate or glucuronide conjugates and N,N-didesethyl analogue are inactive metabolites.

Route of elimination

More than 95% of total dose is excreted as metabolites and the excretion via urine and feces is approximately equal. Renal elimination accounts for 50% of total elimination, where sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues can be detected in the urine. Unconjugated forms of sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues are excreted into feces, and fecal elimination accounts for 40% of the total elimination of the drug.

Half life

The terminal half-life for parent drug is 11.5 hours following single dose and 17 hours at steady state.

Clearance
Not Available
Toxicity

Most commonly observed adverse effects are nausea, vomiting, headache, dizziness and fatigue that usually appear in the beginning of initial therapy. Less frequent side effects (1 to 10%) include anorexia, abdominal pain, constipation or diarrhoea, insomnia, oedema, flushing, nasal congestion and hypotension. Orthostatic hypotension may result in faintness or syncope Label. Quinagolide demonstrates carcinogenic potential in animal studies but with no known relevance in humans. It is not demonstrated to be embryotoxic or teratogenic, but it is associated with reduced pregnancy rates 6. Oral LD50 values in mouse, rat and rabbit are 300 mg/kg, 980 mg/kg and 3200 mg/kg, respectively MSDS.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcepromazineThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Acepromazine.
AceprometazineThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Aceprometazine.
AcetophenazineThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Acetophenazine.
AlimemazineThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Alimemazine.
AlizaprideThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Alizapride.
AmisulprideThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Amisulpride.
AmoxapineThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Amoxapine.
AmperozideThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Amperozide.
ApomorphineThe risk or severity of adverse effects can be decreased when Apomorphine is combined with Quinagolide.
AripiprazoleThe therapeutic efficacy of Quinagolide can be decreased when used in combination with Aripiprazole.
Additional Data Available
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  • Severity
    Severity

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Food Interactions
Not Available

References

General References
  1. Barlier A, Jaquet P: Quinagolide--a valuable treatment option for hyperprolactinaemia. Eur J Endocrinol. 2006 Feb;154(2):187-95. [PubMed:16452531]
  2. Di Sarno A, Landi ML, Marzullo P, Di Somma C, Pivonello R, Cerbone G, Lombardi G, Colao A: The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas. Clin Endocrinol (Oxf). 2000 Jul;53(1):53-60. [PubMed:10931080]
  3. Schultz PN, Ginsberg L, McCutcheon IE, Samaan N, Leavens M, Gagel RF: Quinagolide in the management of prolactinoma. Pituitary. 2000 Dec;3(4):239-49. [PubMed:11788012]
  4. Busso C, Fernandez-Sanchez M, Garcia-Velasco JA, Landeras J, Ballesteros A, Munoz E, Gonzalez S, Simon C, Arce JC, Pellicer A: The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double-blind, placebo-controlled trial. Hum Reprod. 2010 Apr;25(4):995-1004. doi: 10.1093/humrep/deq005. Epub 2010 Feb 6. [PubMed:20139430]
  5. 32. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 397-398). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
  6. DRUG NAME: Quinagolide - BC Cancer Agency [Link]
  7. NORPROLAC® (quinagolide) Product information [Link]
External Links
PubChem Compound
3086401
PubChem Substance
310265024
ChemSpider
2343034
BindingDB
50225362
ChEBI
135627
ChEMBL
CHEMBL290962
Wikipedia
Quinagolide
ATC Codes
G02CB04 — Quinagolide
AHFS Codes
  • 92:00.00 — Miscellaneous Therapeutic Agents
FDA label
Download (301 KB)
MSDS
Download (78.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedPreventionOvarian Hyperstimulation Syndrome1
2CompletedTreatmentOvarian Hyperstimulation Syndrome1
2Not Yet RecruitingTreatmentEndometriosis1
2RecruitingTreatmentEndometriosis-related Pain1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral0.025 mg
TabletOral0.05 mg
TabletOral0.075 mg
TabletOral0.15 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)231-237FDA Label/Product monograph
water solubilitySparingly soluble in water (0.2%) FDA Label/Product monograph
Predicted Properties
PropertyValueSource
Water Solubility0.154 mg/mLALOGPS
logP2.56ALOGPS
logP2.5ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)10.2ChemAxon
pKa (Strongest Basic)8.22ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area72.88 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity109.66 m3·mol-1ChemAxon
Polarizability44.11 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzoquinolines. These are organic compounds containing a benzene fused to a quinoline ring system.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Benzoquinolines
Direct Parent
Benzoquinolines
Alternative Parents
Tetralins / Aralkylamines / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Sulfuric acid diamides / Piperidines / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds
show 2 more
Substituents
Benzoquinoline / Tetralin / 1-hydroxy-4-unsubstituted benzenoid / 1-hydroxy-2-unsubstituted benzenoid / Aralkylamine / Sulfuric acid diamide / Piperidine / Benzenoid / Organic sulfuric acid or derivatives / Tertiary amine
show 11 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.

Components:
References
  1. Barlier A, Jaquet P: Quinagolide--a valuable treatment option for hyperprolactinaemia. Eur J Endocrinol. 2006 Feb;154(2):187-95. [PubMed:16452531]

Drug created on September 16, 2015 12:24 / Updated on June 16, 2019 06:59