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Showing drug card for Nafarelin (DB00666)

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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:05:42
Primary Accession Number DB00666
Secondary Accession Number
  • APRD01129
Name Nafarelin
Drug Type
  • Approved
  • Small Molecule
Description 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]
Synonyms
  1. Nafarelin acetate
Brand Names
  1. Synarel
Brand Mixtures Not Available
Chemical IUPAC Name N-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide
Chemical Formula C66H83N17O13
Chemical Structure Structure
CAS Registry Number 76932-56-4
InChI Identifier InChI=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)/f/h68,70-71,73,75-82H,67,69H2/b68-66+
InChI Key RWHUEXWOYVBUCI-TXVVHJTMDE
KEGG Drug Not Available
KEGG Compound C07613 Link Image
PubChem Compound 16129618 Link Image
PubChem Substance 9815 Link Image
ChEBI ID Not Available
PharmGKB ID PA450574 Link Image
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] 02188783 Link Image
RxList Link http://www.rxlist.com/cgi/generic2/nafarelin.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Nafarelin Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Not Available
Average Molecular Weight 1322.4713
Monoisotopic Molecular Weight 1321.6356
State Solid
Melting Point Not Available
Experimental Water Solubility Not Available Source: PhysProp
Predicted Water Solubility 1.66e-02 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity Not Available Source: PhysProp
Predicted LogP 1.21 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -4.90 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES [H]\N=C(/N)NCCC[C@@H](NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC1=CC2=CC=CC=C2C=C1)NC(=O)[C@@H](CC1=CC=C(O)C=C1)NC(=O)[C@@H](CO)NC(=O)[C@H](CC1=CNC2=CC=CC=C12)NC(=O)[C@H](CC1=CNC=N1)NC(=O)[C@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Canonical SMILES [H]N=C(N)NCCCC(NC(=O)C(CC(C)C)NC(=O)C(CC1=CC2=CC=CC=C2C=C1)NC(=O)C(CC1=CC=C(O)C=C1)NC(=O)C(CO)NC(=O)C(CC1=CNC2=CC=CC=C12)NC(=O)C(CC1=CNC=N1)NC(=O)C1CCC(=O)N1)C(=O)N1CCCC1C(=O)NCC(N)=O
Drug Category
  • Antiendometriotic agent
  • Fertility Agents, Female
  • Gonadotropin-releasing hormones
ATC Codes
AHFS Codes
  • 68:18.00
Indication For treatment of gonadotropin-dependent precocious puberty in children of both sexes and for the treatment of endometriosis.
Pharmacology Nafarelin is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, LH and FSH, resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland. Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. After nafarelin therapy is discontinued, pituitary and ovarian function normalize and estradiol serum concentrations increase to pretreatment levels. Recurrences of endometriosis are frequent after cessation of any hormonal therapy and after surgery that leaves the ovaries and/or uterus intact.
Mechanism of Action 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. A reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes occur. 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. Nafarelin does not abolish the underlying pathophysiology of endometriosis, however.
Absorption Rapidly 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.
Toxicity In 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.
Protein Binding Approximately 80%.
Biotransformation Enzymatic hydrolysis.
Half Life 3 hours
Dosage Forms
Form Route
Aerosol, metered Nasal
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions Not Available
Food Interactions Not Available
Pathways Not Available
General References
  1. Wikipedia Link Image
  2. RxList Link Image
Organisms Affected
  • Humans and other mammals
Targets
  1. Gonadotropin-releasing hormone receptor
  2. Gonadotropin-releasing hormone II receptor
Drug Target 1 [top]
Target 1 ID 226
Target 1 Name Gonadotropin-releasing hormone receptor
Target 1 Synonyms
  1. GnRH receptor
  2. GnRH-R
Target 1 Gene Name GNRHR
Target 1 Protein Sequence >Gonadotropin-releasing hormone receptor 
MANSASPEQNQNHCSAINNSIPLMQGNLPTLTLSGKIRVTVTFFLFLLSATFNASFLLKL
QKWTQKKEKGKKLSRMKLLLKHLTLANLLETLIVMPLDGMWNITVQWYAGELLCKVLSYL
KLFSMYAPAFMMVVISLDRSLAITRPLALKSNSKVGQSMVGLAWILSSVFAGPQLYIFRM
IHLADSSGQTKVFSQCVTHCSFSQWWHQAFYNFFTFSCLFIIPLFIMLICNAKIIFTLTR
VLHQDPHELQLNQSKNNIPRARLKTLKMTVAFATSFTVCWTPYYVLGIWYWFDPEMLNRL
SDPVNHFFFLFAFLNPCFDPLIYGYFSL
Target 1 Number of Residues 333
Target 1 Molecular Weight 37731
Target 1 Theoretical pI 9.93
Target 1 GO Classification
Function
protein-hormone receptor activity
gonadotropin-releasing hormone receptor activity
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
Process
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway
Component
cell
membrane
intrinsic to membrane
integral to membrane
Target 1 General Function Involved in rhodopsin-like receptor activity
Target 1 Specific Function Receptor for gonadotropin releasing hormone (GnRH) that mediate the action of GnRH to stimulate the secretion of the gonadotropic hormones (LH and FSH). This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act a an inhibitor of GnRH-R signaling
Target 1 Pathways Not Available
Target 1 Reactions Not Available
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • 39-58
  • 78-97
  • 116-137
  • 165-184
  • 213-232
  • 282-300
  • 307-326
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 183422 Link Image
Target 1 UniProtKB/Swiss-Prot ID P30968 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name GNRHR_HUMAN Link Image
Target 1 PDB ID Not Available
Target 1 Cellular Location
  • Membrane
  • multi-pass membrane protein
Target 1 Gene Sequence >987 bp 
ATGGCAAACAGTGCCTCTCCTGAACAGAATCAAAATCACTGTTCAGCCATCAACAACAGC
ATCCCACTGATGCAGGGCAACCTCCCCACTCTGACCTTGTCTGGAAAGATCCGAGTGACG
GTTACTTTCTTCCTTTTTCTGCTCTCTGCGACCTTTAATGCTTCTTTCTTGTTGAAACTT
CAGAAGTGGACACAGAAGAAAGAGAAAGGGAAAAAGCTCTCAAGAATGAAGCTGCTCTTA
AAACATCTGACCTTAGCCAACCTGTTGGAGACTCTGATTGTCATGCCACTGGATGGGATG
TGGAACATTACAGTCCAATGGTATGCTGGAGAGTTACTCTGCAAAGTTCTCAGTTATCTA
AAGCTTTTCTCCATGTATGCCCCAGCCTTCATGATGGTGGTGATCAGCCTGGACCGCTCC
CTGGCTATCACGAGGCCCCTAGCTTTGAAAAGCAACAGCAAAGTCGGACAGTCCATGGTT
GGCCTGGCCTGGATCCTCAGTAGTGTCTTTGCAGGACCACAGTTATACATCTTCAGGATG
ATTCATCTAGCAGACAGCTCTGGACAGACAAAAGTTTTCTCTCAATGTGTAACACACTGC
AGTTTTTCACAATGGTGGCATCAAGCATTTTATAACTTTTTCACCTTCAGCTGCCTCTTC
ATCATCCCTCTTTTCATCATGCTGATCTGCAATGCAAAAATCATCTTCACCCTGACACGG
GTCCTTCATCAGGACCCCCACGAACTACAACTGAATCAGTCCAAGAACAATATACCAAGA
GCACGGCTGAAGACTCTAAAAATGACGGTTGCATTTGCCACTTCATTTACTGTCTGCTGG
ACTCCCTACTATGTCCTAGGAATTTGGTATTGGTTTGATCCTGAAATGTTAAACAGGTTG
TCAGACCCAGTAAATCACTTCTTCTTTCTCTTTGCCTTTTTAAACCCATGCTTTGATCCA
CTTATCTATGGATATTTTTCTCTGTGA
Target 1 GenBank Gene ID
Target 1 GeneCard ID GNRHR Link Image
Target 1 GenAtlas ID GNRHR Link Image
Target 1 HGNC ID HGNC:4421 Link Image
Target 1 Chromosome Location 4
Target 1 Locus 4q21.2
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Kottler ML, Bergametti F, Carre MC, Morice S, Decoret E, Lagarde JP, Starzec A, Counis R: Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene. Eur J Endocrinol. 1999 Jun;140(6):561-9. [PubMed Link Image]
  2. Kakar SS, Musgrove LC, Devor DC, Sellers JC, Neill JD: Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem Biophys Res Commun. 1992 Nov 30;189(1):289-95. [PubMed Link Image]
  3. Kakar SS, Grizzle WE, Neill JD: The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. Mol Cell Endocrinol. 1994 Dec;106(1-2):145-9. [PubMed Link Image]
  4. Chi L, Zhou W, Prikhozhan A, Flanagan C, Davidson JS, Golembo M, Illing N, Millar RP, Sealfon SC: Cloning and characterization of the human GnRH receptor. Mol Cell Endocrinol. 1993 Feb;91(1-2):R1-6. [PubMed Link Image]
  5. Grosse R, Schoneberg T, Schultz G, Gudermann T: Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor. Mol Endocrinol. 1997 Aug;11(9):1305-18. [PubMed Link Image]
  6. Kakar SS: Molecular structure of the human gonadotropin-releasing hormone receptor gene. Eur J Endocrinol. 1997 Aug;137(2):183-92. [PubMed Link Image]
Target 1 Drug References
  1. Barbieri RL: Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol. 1990 Feb;162(2):581-5. [PubMed Link Image]
Drug Target 2 [top]
Target 2 ID 524
Target 2 Name Gonadotropin-releasing hormone II receptor
Target 2 Synonyms
  1. GnRH-II-R
  2. Type II GnRH receptor
Target 2 Gene Name GNRHR2
Target 2 Protein Sequence Not Available
Target 2 Number of Residues 0
Target 2 Molecular Weight 41576
Target 2 Theoretical pI 9.68
Target 2 GO Classification
Function
protein-hormone receptor activity
gonadotropin-releasing hormone receptor activity
signal transducer activity
receptor activity
transmembrane receptor activity
G-protein coupled receptor activity
rhodopsin-like receptor activity
Process
cellular process
cell communication
signal transduction
cell surface receptor linked signal transduction
G-protein coupled receptor protein signaling pathway
Component
cell
membrane
intrinsic to membrane
integral to membrane
Target 2 General Function Involved in rhodopsin-like receptor activity
Target 2 Specific Function Receptor for gonadotropin releasing hormone II (GnRH II). This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system (Potential)
Target 2 Pathways Not Available
Target 2 Reactions Not Available
Target 2 Pfam Domain Function
Target 2 Signals
  • None
Target 2 Transmembrane Regions
  • 41-60
  • 77-96
  • 115-136
  • 161-178
  • 205-224
  • 279-297
  • 304-323
Target 2 Essentiality Non-Essential
Target 2 GenBank ID Protein 16589056 Link Image
Target 2 UniProtKB/Swiss-Prot ID Q96P88 Link Image
Target 2 UniProtKB/Swiss-Prot Entry Name GNRR2_HUMAN Link Image
Target 2 PDB ID Not Available
Target 2 Cellular Location
  • Membrane
  • multi-pass membrane protein
Target 2 Gene Sequence >1140 bp 
CATGTCTGCAGGCAACGGCACCCCTTGGGGTCAGCAGCGGGGGAGGAGGTCTGGGCTGGA
TCAGGAGTGGAGGTGGAGGGCTCAGAGCTGCCCACCTTCTCGGCAGCAGCCAAGGTCCGA
GTGGGAGTGACCATTGTGCTGTTTGTTTCTTCGGCTGGAGGGAACCTGGCAGTCCTGTGG
TCAGTGACACGGCGGGAACCCAGCCAGCTCCGCCCCTCTCCGGTCAGGAGACTCTTCATC
CATTTAGCAGCCGCCGACTTACTAGTCACTTTTGTGGTTATGCCCCTAGATGCCACCTGG
AATATCACTGTTCAATGGCTGGCTGTGGACATCGCATGTCGGACACTGATGTTCCTGAAA
CTAATGGCCACGTATTCTGCAGCTTTCCTGCCTGTGGTCATTGGATTGGACCGCCAGGCA
GCAGTACTCAACCCGCTTGGATCCCGTTCAGGTGTAAGGAAACTTCTGGGGGCAGCCTGG
GGACTTAGTTTCCTGCTTGCCTTCCCCCAGCTGTTCCTGTTCCACACGGTCCACTGAGCT
GGCCCAGTCCCTTTCACTCAGTGTGTCACCAAAGGCAGCTTCAAGGCTCAATGGCAAGAG
ACCACCTATAACCTCTTCACCTTCTGCTGCCTCTTTCTGCTGCCACTGACTGCCATGGCC
ATCTGCTATAGCCGCATTGTCCTCAGTGTGTCCAGGCCCCAGACAAGGAAGGGGAGCCAT
GCCCCTGCTGGTGAATTTGCCCTCCCCCGCTCCTTTGACAATTGTCCCCGTGTTCGTCTC
CGGGCCCTGAGACTGGCCCTGCTTATCTTGCTGACCTTCATCCTCTGCTGGACACCTTAT
TACCTACTGGGTATGTGGTACTGGTTCTCCCCCACCATGCTAACTGAAGTCCCTCCCAGC
CTGAGCCACATCCTTTTCCTCTTGGGCCTCCTCAATGCTCCTTTGGATCCTCTCCTCTAT
GGGGCCTTCACCCTTGGCTGCCGAAGAGGGCACCAAGAACTTAGTATAGACTCTTCTAAA
GAAGGGTCTGGGAGAATGCTCCAAGAGGAGATTCATGCCTTTAGACAGCTGGAAGTACAA
AAAACTGTGACATCAAGAAGGGCAGGAGAAACAAAAGGCATTTCTATAACATCTATCTGA
Target 2 GenBank Gene ID
Target 2 GeneCard ID GNRHR2 Link Image
Target 2 GenAtlas ID GNRHR2 Link Image
Target 2 HGNC ID HGNC:16341 Link Image
Target 2 Chromosome Location 1
Target 2 Locus 1q12
Target 2 SNPs SNPJam Report Link Image
Target 2 General References
  1. Faurholm B, Millar RP, Katz AA: The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci. Genomics. 2001 Nov;78(1-2):15-8. [PubMed Link Image]
  2. Neill JD: GnRH and GnRH receptor genes in the human genome. Endocrinology. 2002 Mar;143(3):737-43. [PubMed Link Image]
Target 2 Drug References
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed Link Image]
  2. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]

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