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J. Biol. Chem., Vol. 279, Issue 33, 34115-34122, August 13, 2004

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Species Selectivity of Nonpeptide Antagonists of the Gonadotropinreleasing Hormone Receptor Is Determined by Residues in Extracellular Loops II and III and the Amino Terminus^*

Greg J. Reinhart, Qiu Xie, Xin-Jun Liu, Yun-Fei Zhu¶, Jun Fan||, Chen Chen¶, and R. Scott Struthers**

From the Departments of Endocrinology, Peptide Chemistry, ^¶Medicinal Chemistry, and ^||Molecular Biology, Neurocrine Biosciences Inc., San Diego, California 92121

Efforts to develop orally available gonadotropin-releasing hormone (GnRH) receptor antagonists have led to the discovery of several classes of potent nonpeptide antagonists. Here we investigated molecular interactions of three classes of nonpeptide antagonists with human, rat, and macaque GnRH receptors. Although all are high affinity ligands of the human receptor (K_i <5 nM), these compounds show reduced affinity for the macaque receptor and bind only weakly (K_i >1 µM) to the rat receptor. To identify residues responsible for this selectivity, a series of chimeric receptors and mutant receptors was constructed and evaluated for nonpeptide binding. Surprisingly, 4 key residues located in the amino terminus (Met-24) and extracellular loops II (Ser-203, Gln-208) and III (Leu-300) of the GnRH receptor appear to be primarily responsible for species-selective binding. Comparisons of reciprocal mutations suggest that these may not be direct contacts but rather may be involved in organizing extracellular portions of the receptor. These data are novel because most previous reports of residues involved in binding of nonpeptide ligands to peptide-activated G protein-coupled receptors, including the GnRH receptor as well as mono-amine receptors, have identified binding sites in the transmembrane regions.

Received for publication, April 22, 2004 , and in revised form, May 21, 2004.

^* This work was supported in part by National Institutes of Health Grants 1-R43-HD38625-01 and 2-R44-HD38625-02. 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.

^** To whom correspondence should be addressed: Neurocrine Biosciences Inc., 10555 Science Center Dr., San Diego, CA 92121. Tel.: 858-658-7740; Fax: 858-658-7601; E-mail: sstruthers{at}neurocrine.com.

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