Structure–activity relationship study on small peptidic GPR54 agonists

Tomita, Kenji; Niida, Ayumu; Oishi, Shinya; Ohno, Hiroaki; Jérôme, Christine; Navenot, Jean-Marc; Wang, Zixuan; Peiper, Stephen C.; Fujii, Nobutaka

doi:10.1016/j.bmc.2006.07.009

Cited by 47 publications

(55 citation statements)

References 23 publications

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“…The essential role of the C-terminal residue was expected, because previous studies have shown the indispensable role of this amino acid to maintain an appropriate function not only of kisspeptin (Ohtaki et al, 2001;Niida et al, 2006;Orsini et al, 2007) but also of other members of the RF-amide family of peptides, which includes prolactin-releasing peptide and neuropeptide FF, where the C-terminal Arg-Phe is also critical for their biological activity (Mazarguil et al, 2001;Boyle et al, 2005). However, the native C-terminal phenylalanine residue can be replaced by different aromatic moieties, such as tyrosine, tryptophan, substituted phenylalanine, or naphthylalanine, without significant loss of potency or efficacy of Arg-Phe-amide peptides (Mazarguil et al, 2001;Boyle et al, 2005;Tomita et al, 2006). Conversely, replacement of the C-terminal phenylalanine by saturated side-chain residues such as cyclohexylalanine suppresses the biological activity of kp-10 (Orsini et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, only a limited number of reports have analyzed the structure-activity relationships of kisspeptins and kiss1r Tomita et al, 2006Tomita et al, , 2007aTomita et al, ,b, 2008Orsini et al, 2007), and none has integrated the chemical structure of this peptide family, its functional features in cell models in vitro, and its effects in vivo in a physiologically relevant target.…”

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confidence: 99%

“…Studies from two different groups have analyzed the structure-activity relationships of Kp-10 (Niida et al, 2006;Tomita et al, 2006Tomita et al, , 2007aTomita et al, ,b, 2008Orsini et al, 2007). These analyses indicate that the nature and the orientation of the side chains of the five C-terminal residues are important for receptor binding and activation, whereas the N-terminal amino acids are more tolerant to substitution by L-alanine or enantiomer residues Orsini et al, 2007).…”

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confidence: 99%

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In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

Gutiérrez-Pascual¹,

Leprince²,

Martínez-Fuentes³

et al. 2009

Mol Pharmacol

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Kisspeptins, the natural ligands of the G protein-coupled receptor KISS1R, comprise a family of related peptides derived from the proteolytic processing of a common precursor encoded by the KISS1 gene. Among those, Kisspeptin-10 (Kp-10) contains the basic residues to retain full functional activity and exhibits higher receptor affinity and biopotency than longer forms of the peptide. Although kisspeptins were first characterized by their ability to inhibit tumor metastasis, recent studies have revealed that the KISS1/KISS1R system plays an essential role in the neuroendocrine control of the reproductive axis. In this context, development and functional analysis of Kp-10 analogs may help in the search for new agonists and antagonists as valuable tools to manipulate the KISS1/KISS1R system and hence fertility. We report herein functional and structural analyses of a series of Ala-substituted rat kp-10 analogs, involving [Ca 2ϩ

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

Gutiérrez-Pascual¹,

Leprince²,

Martínez-Fuentes³

et al. 2009

Mol Pharmacol

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“…The amino acid sequence of suncus kisspeptin and its core sequence were deduced according to the cDNA sequence of the musk shrew. (34,37,38). Presumed ovulation was determined by microscopic examination of the fungiform corpus luteum formation in ovaries of individual animals.…”

Section: Methodsmentioning

confidence: 99%

Kisspeptin neurons mediate reflex ovulation in the musk shrew ( Suncus murinus )

Inoue

Sasagawa

Ikai

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The present study investigated whether kisspeptin-G protein-coupled receptor 54 (GPR54) signaling plays a role in mediating mating-induced ovulation in the musk shrew (Suncus murinus), a reflex ovulator. For this purpose, we cloned suncus Kiss1 and Gpr54 cDNA from the hypothalamus and found that suncus kisspeptin (sKp) consists of 29 amino acid residues (sKp-29). Injection of exogenous sKp-29 mimicked the mating stimulus to induce follicular maturation and ovulation. Administration of several kisspeptins and GPR54 agonists also induced presumed ovulation in a dose-dependent manner, and Gpr54 mRNA was distributed in the hypothalamus, showing that kisspeptins induce ovulation through binding to GPR54. The sKp-29-induced ovulation was blocked completely by pretreatment with a gonadotropin-releasing hormone (GnRH) antagonist, suggesting that kisspeptin activates GnRH neurons to induce ovulation in the musk shrew. In addition, in situ hybridization revealed that Kiss1-expressing cells are located in the medial preoptic area (POA) and arcuate nucleus in the musk shrew hypothalamus. The number of Kiss1-expressing cells in the POA or arcuate nucleus was up-regulated or downregulated by estradiol, suggesting that kisspeptin neurons in these regions were the targets of the estrogen feedback action. Finally, mating stimulus largely induced c-Fos expression in Kiss1-positive cells in the POA, indicating that the mating stimulus activates POA kisspeptin neurons to induce ovulation. Taken together, these results indicate that kisspeptin-GPR54 signaling plays a role in the induction of ovulation in the musk shrew, a reflex ovulator, as it does in spontaneous ovulators.brain | copulation | Kiss1r | metastin | ovary

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“…A series of pentapeptide-based GPR54 agonists have been described [44,45]. Furthermore, smallmolecule GPR54 agonists have been identified, although detailed results of these have not been published [46].…”

Section: What Advantages Might Kisspeptin Have Over Existing Therapies?mentioning

confidence: 99%

Does Kisspeptin signaling offer a new way to treat infertility?

Jayasena

Dhillo

Bloom

2009

Expert Review of Obstetrics & Gynecology

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Structure–activity relationship study on small peptidic GPR54 agonists

Cited by 47 publications

References 23 publications

In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

Kisspeptin neurons mediate reflex ovulation in the musk shrew ( Suncus murinus )

Does Kisspeptin signaling offer a new way to treat infertility?

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