HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 19, 13226-13233, May 12, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/19/13226    most recent M600601200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yanofsky, S. D. Articles by Barrett, R. W. Search for Related Content PubMed PubMed Citation Articles by Yanofsky, S. D. Articles by Barrett, R. W. Social Bookmarking                      What's this?

Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists^*

Stephen D. Yanofsky¹, Emily S. Shen, Frank Holden, Erik Whitehorn, Barbara Aguilar, Emily Tate, Christopher P. Holmes, Randall Scheuerman, Derek MacLean, May M. Wu, Donald E. Frail, Francisco J. López, Richard Winneker, Brian J. Arey, and Ronald W. Barrett

From the Affymax, Inc., Palo Alto, California 94304 and Women's Health and Musculoskeletal Biology, Wyeth Pharmaceuticals, Collegeville, Pennsylvania, 19426-3930

The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC_50's = 20 µM) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC₅₀ = 2 nM) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC₅₀ = 980 nM) and estradiol production from primary rat ovarian granulosa cells (EC₅₀ = 10.5 nM). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy.

Received for publication, January 20, 2006 , and in revised form, March 10, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 3781 Nathan Way, Palo Alto, CA 94303. Tel.: 650-852-0440; Fax: 650-852-9394; E-mail: syanofsky{at}sbcglobal.net.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. van de Lagemaat, C.M. Timmers, J. Kelder, C. van Koppen, S. Mosselman, and R.G.J.M. Hanssen Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor Hum. Reprod., March 1, 2009; 24(3): 640 - 648. [Abstract] [Full Text] [PDF]