Linked Life Data

21184806

Source:http://linkedlifedata.com/resource/pubmed/id/21184806

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2011-2-14
pubmed:abstractText
High quality gamete production in males and females requires the pituitary gonadotropin follicle stimulating hormone (FSH). In this report a novel chemical class of small molecule inhibitors of FSH receptor (FSHR) is described. ADX61623, a negative allosteric modulator (NAM), increased the affinity of interaction between (125)I-hFSH and human FSHR (hFSHR) five fold. This form of FSHR occupied simultaneously by FSH and ADX61623 was inactive for cAMP and progesterone production in primary cultures of rat granulosa cells. In contrast, ADX61623 did not block estrogen production. This demonstrates for the first time, biased antagonism at the FSHR. To determine if ADX61623 blocked FSH induction of follicle development in vivo, a bioassay to measure follicular development and oocyte production in immature female rats was validated. ADX61623 was not completely effective in blocking FSH induced follicular development in vivo at doses up to 100mg/kg as oocyte production and ovarian weight gain were only moderately reduced. These data illustrate that FSHR couples to multiple signaling pathways in vivo. Suppression of one pool of FSHR uncouples G?s and cAMP production, and decreases progesterone production. Occupancy of another pool of FSHR sensitizes granulosa cells to FSH induced estradiol production. Therefore, ADX61623 is a useful tool to investigate further the mechanism of the FSHR signaling dichotomy. This may lead to a greater understanding of the signaling infrastructure which enables estrogen biosynthesis and may prove useful in treating estrogen dependent disease.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1872-8057
pubmed:author
pubmed:copyrightInfo
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
20
pubmed:volume
333
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
143-50
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
A negative allosteric modulator demonstrates biased antagonism of the follicle stimulating hormone receptor.
pubmed:affiliation
Wadsworth Center, David Axelrod Institute for Public Health, New York State Department of Health, Albany, NY 12208, United States. JDias@uamail.albany.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural