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J. Biol. Chem., Vol. 282, Issue 35, 25425-25435, August 31, 2007

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R3(B23–27)R/I5 Chimeric Peptide, a Selective Antagonist for GPCR135 and GPCR142 over Relaxin Receptor LGR7

IN VITRO AND IN VIVO CHARACTERIZATION^*

Chester Kuei, Steven Sutton, Pascal Bonaventure, Cindy Pudiak, Jonathan Shelton, Jessica Zhu, Diane Nepomuceno, Jiejun Wu, Jingcai Chen, Fredrik Kamme, Mark Seierstad, Michael D. Hack, Ross A. D. Bathgate, Mohammed Akhter Hossain, John D. Wade, John Atack, Timothy W. Lovenberg, and Changlu Liu¹

From the Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, California 92121 and the Howard Florey Institute, University of Melbourne, Victoria 3010, Australia

Both relaxin-3 and its receptor (GPCR135) are expressed predominantly in brain regions known to play important roles in processing sensory signals. Recent studies have shown that relaxin-3 is involved in the regulation of stress and feeding behaviors. The mechanisms underlying the involvement of relaxin-3/GPCR135 in the regulation of stress, feeding, and other potential functions remain to be studied. Because relaxin-3 also activates the relaxin receptor (LGR7), which is also expressed in the brain, selective GPCR135 agonists and antagonists are crucial to the study of the physiological functions of relaxin-3 and GPCR135 in vivo. Previously, we reported the creation of a selective GPCR135 agonist (a chimeric relaxin-3/INSL5 peptide designated R3/I5). In this report, we describe the creation of a high affinity antagonist for GPCR135 and GPCR142 over LGR7. This GPCR135 antagonist, R3(B23–27)R/I5, consists of the relaxin-3 B-chain with a replacement of Gly²³ to Arg, a truncation at the C terminus (Gly²⁴-Trp²⁷ deleted), and the A-chain of INSL5. In vitro pharmacological studies showed that R3(B23–27)R/I5 binds to human GPCR135 (IC₅₀ = 0.67 nM) and GPCR142 (IC₅₀ = 2.29 nM) with high affinity and is a potent functional GPCR135 antagonist (pA2 = 9.15) but is not a human LGR7 ligand. Furthermore, R3(B23–27)R/I5 had a similar binding profile at the rat GPCR135 receptor (IC₅₀ = 0.25 nM, pA2 = 9.6) and lacked affinity for the rat LGR7 receptor. When administered to rats intracerebroventricularly, R3(B23–27)R/I5 blocked food intake induced by the GPCR135 selective agonist R3/I5. Thus, R3(B23–27)R/I5 should prove a useful tool for the further delineation of the functions of the relaxin-3/GPCR135 system.

Received for publication, February 16, 2007 , and in revised form, June 28, 2007.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1–3.

¹ To whom correspondence should be addressed: Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121. Tel.: 858-784-3059; Fax: 858-450-2040; E-mail: cliu9{at}prdus.jnj.com.

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