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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2007-1-17
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pubmed:abstractText |
Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3-(2-amino-2-phenylethyl)-1-(2,6-dif...,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channel Blockers,
http://linkedlifedata.com/resource/pubmed/chemical/Gonadotropin-Releasing Hormone,
http://linkedlifedata.com/resource/pubmed/chemical/Inositol Phosphates,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Luteinizing Hormone,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, LHRH,
http://linkedlifedata.com/resource/pubmed/chemical/Thymine
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0013-7227
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pubmed:author |
pubmed-author:BonnevilleAnne KAK,
pubmed-author:BozigianHaig PHP,
pubmed-author:ChenTa-KungTK,
pubmed-author:KohoutTrudy ATA,
pubmed-author:LingNicholasN,
pubmed-author:LiuXin-JunXJ,
pubmed-author:MakiRichard ARA,
pubmed-author:ReinhartGreg JGJ,
pubmed-author:StruthersR ScottRS,
pubmed-author:SullivanSusan KSK,
pubmed-author:XXX,
pubmed-author:XieQuiQ,
pubmed-author:YangWeidongW,
pubmed-author:ZhuYun-FeiYF
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pubmed:issnType |
Print
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pubmed:volume |
148
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
857-67
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17095587-Administration, Oral,
pubmed-meshheading:17095587-Animals,
pubmed-meshheading:17095587-Binding, Competitive,
pubmed-meshheading:17095587-Binding Sites,
pubmed-meshheading:17095587-Calcium Channel Blockers,
pubmed-meshheading:17095587-Cell Line,
pubmed-meshheading:17095587-Enzyme Activation,
pubmed-meshheading:17095587-Gonadotropin-Releasing Hormone,
pubmed-meshheading:17095587-Histamine Release,
pubmed-meshheading:17095587-Humans,
pubmed-meshheading:17095587-Inositol Phosphates,
pubmed-meshheading:17095587-Ligands,
pubmed-meshheading:17095587-Luteinizing Hormone,
pubmed-meshheading:17095587-Macaca,
pubmed-meshheading:17095587-Male,
pubmed-meshheading:17095587-Mast Cells,
pubmed-meshheading:17095587-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:17095587-Mitogen-Activated Protein Kinase 3,
pubmed-meshheading:17095587-Orchiectomy,
pubmed-meshheading:17095587-Receptors, LHRH,
pubmed-meshheading:17095587-Thymine
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pubmed:year |
2007
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pubmed:articleTitle |
Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.
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pubmed:affiliation |
Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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