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Record Information
Version2.0
Creation Date2009-07-21 20:27:23 UTC
Update Date2014-12-24 20:25:52 UTC
Accession NumberT3D2855
Identification
Common NameNafarelin
ClassSmall Molecule
DescriptionNafarelin is only found in individuals that have used or taken this drug. It is a potent synthetic agonist of gonadotropin-releasing hormone with 3-(2-naphthyl)-D-alanine substitution at residue 6. Nafarelin has been used in the treatments of central precocious puberty and endometriosis. [PubChem]Like GnRH, initial or intermittent administration of nafarelin stimulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases production of estradiol in females and testosterone in both sexes. However, with continuous daily administration, nafarelin continuously occupies the GnRH receptor, leading to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. This causes a significant and sustained decline in the production of LH and FSH. A decline in gonadotropin production and release causes a dramatic reversible decrease in synthesis of estradiol, progesterone, and testosterone by the ovaries or testes. Like normal endometrium, endometriotic implants contain estrogen receptors. Estrogen stimulates the growth of endometrium. Use of nafarelin induces anovulation and amenorrhea and decreases serum concentrations of estradiol to the postmenopausal range, which induces atrophy of endometriotic implants. However, nafarelin does not abolish the underlying pathophysiology of endometriosis. In children with central precocious puberty receiving nafarelin, serum LH, testosterone, and estradiol concentrations return to prepubertal levels. This results in the supression of secondary sexual characteristics and decrased rate of linear growth and skeletal maturation. Following disconinuation of nafarelin, the effects of the drug is reversed, meaning FSH and LH concentrations usually return to pretreatment levels.
Compound Type
  • Amide
  • Amine
  • Antiendometriotic Agent
  • Drug
  • Fertility Agent, Female
  • Gonadotropin-Releasing Hormone
  • Gonadotropin-releasing hormone agonist
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Nafarelil
Nafarelin acetate
Nafarelina
Nafaréline
Nafarelinum
Nasanyl
Synarel
Synarela
Synrelina
Chemical FormulaC66H83N17O13
Average Molecular Mass1322.471 g/mol
Monoisotopic Mass1321.636 g/mol
CAS Registry Number76932-56-4
IUPAC NameN-(5-carbamimidamido-1-{2-[(carbamoylmethyl)carbamoyl]pyrrolidin-1-yl}-1-oxopentan-2-yl)-2-{2-[2-(3-hydroxy-2-{2-[3-(1H-imidazol-4-yl)-2-[(5-oxopyrrolidin-2-yl)formamido]propanamido]-3-(1H-indol-3-yl)propanamido}propanamido)-3-(4-hydroxyphenyl)propanamido]-3-(naphthalen-2-yl)propanamido}-4-methylpentanamide
Traditional Namenafarelin
SMILESCC(C)CC(N=C(O)C(CC1=CC2=CC=CC=C2C=C1)N=C(O)C(CC1=CC=C(O)C=C1)N=C(O)C(CO)N=C(O)C(CC1=CNC2=CC=CC=C12)N=C(O)C(CC1=CN=CN1)N=C(O)C1CCC(O)=N1)C(O)=NC(CCCNC(N)=N)C(=O)N1CCCC1C(O)=NCC(O)=N
InChI IdentifierInChI=1/C66H83N17O13/c1-36(2)25-48(58(89)76-47(13-7-23-71-66(68)69)65(96)83-24-8-14-54(83)64(95)73-33-55(67)86)77-60(91)50(28-38-15-18-39-9-3-4-10-40(39)26-38)78-59(90)49(27-37-16-19-43(85)20-17-37)79-63(94)53(34-84)82-61(92)51(29-41-31-72-45-12-6-5-11-44(41)45)80-62(93)52(30-42-32-70-35-74-42)81-57(88)46-21-22-56(87)75-46/h3-6,9-12,15-20,26,31-32,35-36,46-54,72,84-85H,7-8,13-14,21-25,27-30,33-34H2,1-2H3,(H2,67,86)(H,70,74)(H,73,95)(H,75,87)(H,76,89)(H,77,91)(H,78,90)(H,79,94)(H,80,93)(H,81,88)(H,82,92)(H4,68,69,71)
InChI KeyInChIKey=RWHUEXWOYVBUCI-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
KingdomOrganic compounds
Super ClassOrganic Polymers
ClassPolypeptides
Sub ClassNot Available
Direct ParentPolypeptides
Alternative Parents
Substituents
  • Polypeptide
  • Alpha peptide
  • Tyrosine or derivatives
  • Phenylalanine or derivatives
  • Histidine or derivatives
  • Leucine or derivatives
  • N-acyl-alpha amino acid or derivatives
  • Proline or derivatives
  • Alpha-amino acid amide
  • Triptan
  • Serine or derivatives
  • N-substituted-alpha-amino acid
  • 3-alkylindole
  • Alpha-amino acid or derivatives
  • Naphthalene
  • Amphetamine or derivatives
  • Indole or derivatives
  • Indole
  • Pyrrolidine carboxylic acid or derivatives
  • N-acylpyrrolidine
  • Pyrrolidine-2-carboxamide
  • 1-hydroxy-2-unsubstituted benzenoid
  • Phenol
  • Monocyclic benzene moiety
  • Fatty amide
  • N-acyl-amine
  • Fatty acyl
  • Benzenoid
  • Substituted pyrrole
  • Pyrrolidone
  • 2-pyrrolidone
  • Azole
  • Pyrrolidine
  • Tertiary carboxylic acid amide
  • Pyrrole
  • Imidazole
  • Heteroaromatic compound
  • Primary carboxylic acid amide
  • Carboxamide group
  • Guanidine
  • Lactam
  • Secondary carboxylic acid amide
  • Carboximidamide
  • Organoheterocyclic compound
  • Azacycle
  • Carboxylic acid derivative
  • Organic nitrogen compound
  • Organooxygen compound
  • Organic oxide
  • Carbonyl group
  • Organopnictogen compound
  • Alcohol
  • Primary alcohol
  • Organonitrogen compound
  • Organic oxygen compound
  • Imine
  • Hydrocarbon derivative
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility1.66e-02 g/L
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.017 g/LALOGPS
logP1.21ALOGPS
logP-2.7ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)9.49ChemAxon
pKa (Strongest Basic)11.92ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count17ChemAxon
Hydrogen Donor Count17ChemAxon
Polar Surface Area472.13 ŲChemAxon
Rotatable Bond Count33ChemAxon
Refractivity357.8 m³·mol⁻¹ChemAxon
Polarizability137.29 ųChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00dr-9037302120-f0facb1967d30439597dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-9011200000-e32adcd953ac1c721212JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00e9-9011100000-0e896538a04b95abd857JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0ukc-2194100000-e5cb37d2eafc7e73ef96JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-11b9-6595010100-3cfda325f415bde10f61JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-052f-9410011130-eb97257a1937988394bcJSpectraViewer
Toxicity Profile
Route of ExposureRapidly absorbed into the systemic circulation after intranasal administration. Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). Not absorbed after oral administration.
Mechanism of ToxicityLike GnRH, initial or intermittent administration of nafarelin stimulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases production of estradiol in females and testosterone in both sexes. However, with continuous daily administration, nafarelin continuously occupies the GnRH receptor, leading to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. This causes a significant and sustained decline in the production of LH and FSH. A decline in gonadotropin production and release causes a dramatic reversible decrease in synthesis of estradiol, progesterone, and testosterone by the ovaries or testes. Like normal endometrium, endometriotic implants contain estrogen receptors. Estrogen stimulates the growth of endometrium. Use of nafarelin induces anovulation and amenorrhea and decreases serum concentrations of estradiol to the postmenopausal range, which induces atrophy of endometriotic implants. However, nafarelin does not abolish the underlying pathophysiology of endometriosis. In children with central precocious puberty receiving nafarelin, serum LH, testosterone, and estradiol concentrations return to prepubertal levels. This results in the supression of secondary sexual characteristics and decrased rate of linear growth and skeletal maturation. Following disconinuation of nafarelin, the effects of the drug is reversed, meaning FSH and LH concentrations usually return to pretreatment levels.
MetabolismEnzymatic hydrolysis. Half Life: 3 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor treatment of central precocious puberty (true precocious puberty, GnRH-dependent precocious precocity, complete isosexual precocity) in children of both sexes and for the treatment of endometriosis.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsIn experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00666
HMDB IDHMDB14804
PubChem Compound ID25077649
ChEMBL IDCHEMBL1201309
ChemSpider ID10605761
KEGG IDC07613
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNafarelin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkNafarelin
References
Synthesis ReferenceNot Available
MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Hugues JN, Cedrin Durnerin IC: Revisiting gonadotrophin-releasing hormone agonist protocols and management of poor ovarian responses to gonadotrophins. Hum Reprod Update. 1998 Jan-Feb;4(1):83-101. [9622415 ]
  3. Garner C: Uses of GnRH agonists. J Obstet Gynecol Neonatal Nurs. 1994 Sep;23(7):563-70. [7996307 ]
  4. Henzl MR: Gonadotropin-releasing hormone analogs: update on new findings. Am J Obstet Gynecol. 1992 Feb;166(2):757-61. [1531579 ]
  5. Burry KA: Nafarelin in the management of endometriosis: quality of life assessment. Am J Obstet Gynecol. 1992 Feb;166(2):735-9. [1531576 ]
  6. Saltiel E, Garabedian-Ruffalo SM: Pharmacologic management of endometriosis. Clin Pharm. 1991 Jul;10(7):518-31. [1830521 ]
  7. Chrisp P, Goa KL: Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions. Drugs. 1990 Apr;39(4):523-51. [2140979 ]
  8. Letassy NA, Thompson DF, Britton ML, Suda RR Sr: Nafarelin acetate: a gonadotropin-releasing hormone agonist for the treatment of endometriosis. DICP. 1990 Dec;24(12):1204-9. [2151003 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Peptide binding
Specific Function:
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.
Gene Name:
GNRHR
Uniprot ID:
P30968
Molecular Weight:
37730.355 Da
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
General Function:
Gonadotropin-releasing hormone receptor activity
Specific Function:
Putative receptor for gonadotropin releasing hormone II (GnRH II) which is most probably non-functional.
Gene Name:
GNRHR2
Uniprot ID:
Q96P88
Molecular Weight:
32536.935 Da
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]