2-Acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats

Kobayashi, Toshimichi; Sasaki, Satoshi; Tomita, Naoki; Fukui, Seiji; Nakayama, Masaharu; Kiba, Atsushi; Kusaka, Masami; Matsumoto, Shimpei; Yamaguchi, Masashi; Itoh, Fumio; Baba, Atsuo

doi:10.1016/j.bmc.2010.05.061

Cited by 24 publications

(20 citation statements)

References 23 publications

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“…PKC is a major mediator of G q protein-initiated signaling. We pretreated GnRH neurons for 2 h with a recently developed GPR54 antagonist, 2-acylamino-4,6-diphenylpyridine derivative (15a) (29), or with a PKC inhibitor, Gö 6983, before stimulating with kisspeptin. Kisspeptin-induced luciferase expression was significantly attenuated in the presence of these inhibitors, thereby suppressing the synchronous transcriptional response of GnRH neurons ( Fig.…”

Section: Synchronous Activation Of Gnrh Transcription and Secretion Bymentioning

confidence: 99%

Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

Choe

Kim

Park

et al. 2013

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

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Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) is essential for pituitary gonadotrope function. Although the importance of pulsatile GnRH secretion has been recognized for several decades, the mechanisms underlying GnRH pulse generation in hypothalamic neural networks remain elusive. Here, we demonstrate the ultradian rhythm of GnRH gene transcription in single GnRH neurons using cultured hypothalamic slices prepared from transgenic mice expressing a GnRH promoter-driven destabilized luciferase reporter. Although GnRH promoter activity in each GnRH neuron exhibited an ultradian pattern of oscillations with a period of ∼10 h, GnRH neuronal cultures exhibited partially synchronized bursts of GnRH transcriptional activity at ∼2-h intervals. Surprisingly, pulsatile administration of kisspeptin, a potent GnRH secretagogue, evoked dramatic synchronous activation of GnRH gene transcription with robust stimulation of pulsatile GnRH secretion. We also addressed the issue of hierarchical interaction between the circadian and ultradian rhythms by using Bmal1 -deficient mice with defective circadian clocks. The circadian molecular oscillator barely affected basal ultradian oscillation of GnRH transcription but was heavily involved in kisspeptin-evoked responses of GnRH neurons. In conclusion, we have clearly shown synchronous bursts of GnRH gene transcription in the hypothalamic GnRH neuronal population in association with episodic neurohormone secretion, thereby providing insight into GnRH pulse generation.

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Section: Synchronous Activation Of Gnrh Transcription and Secretion Bymentioning

confidence: 99%

Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

Choe

Kim

Park

et al. 2013

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

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“…12 More recently, small molecule GPR54 antagonists with a 2-acylamino-4,6-diphenylpyridine scaffold were reported. 13 Intravenous administration of these antagonists to castrated male rats suppressed the plasma LH level.…”

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confidence: 98%

Activation of Neuropeptide FF Receptors by Kisspeptin Receptor Ligands

Oishi

Misu

Tomita

et al. 2010

ACS Med. Chem. Lett.

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Kisspeptin is a member of the RFamide neuropeptide family that is implicated in gonadotropin secretion. Because kisspeptin-GPR54 signaling is implicated in the neuroendocrine regulation of reproduction, GPR54 ligands represent promising therapeutic agents against endocrine secretion disorders. In the present study, the selectivity profiles of GPR54 agonist peptides were investigated for several GPCRs, including RFamide receptors. Kisspeptin-10 exhibited potent binding and activation of neuropeptide FF receptors (NPFFR1 and NPFFR2). In contrast, short peptide agonists bound with much lower affinity to NPFFRs while showing relatively high selectivity toward GPR54. The possible localization of secondary kisspeptin targets was also demonstrated by variation in the levels of GnRH release from the median eminence and the type of GPR54 agonists used. Negligible affinity of the reported NPFFR ligands to GPR54 was observed and indicates the unidirectional cross-reactivity between both ligands.

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“…Compound 15a exhibited high antagonistic activity against KP-10 stimulated calcium release in CHO cells stably expressing GPR54 (Fig. 7c) 118 .…”

Section: Non-peptide Analoguesmentioning

confidence: 96%

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Millar

Newton

2013

Nat Rev Endocrinol

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Reproductive hormones impact on all stages of life from gamete production, fertilisation, fetal development and parturition, neonatal development and puberty through to adulthood and senescence.The reproductive hormone cascade has therefore been the target for the development of numerous drugs which modulate its activity at many levels. As the central regulator of the cascade, gonadotropinreleasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent deseases such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilisation (IVF) protocols. Recently-discovered neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), have also been identified as therapeutic targets and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade, GnRH, KP and NKB.

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2-Acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats

Cited by 24 publications

References 23 publications

Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

Activation of Neuropeptide FF Receptors by Kisspeptin Receptor Ligands

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

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