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Shinya Oishi - One of the best experts on this subject based on the ideXlab platform.

  • Peripheral administration of SB223412, a selective Neurokinin-3 Receptor antagonist, suppresses pulsatile luteinizing hormone secretion by acting on the gonadotropin-releasing hormone pulse generator in estrogen-treated ovariectomized female goats.
    Journal of Reproduction and Development, 2020
    Co-Authors: Takuya Sasaki, Shinya Oishi, Nobutaka Fujii, Koki Yamamoto, Yoshihisa Uenoyama, Tomoya Sonoda, Ryoki Tatebayashi, Yuri Kitagawa, Naoko Inoue, Hiroko Tsukamura
    Abstract:

    Accumulating evidence suggests that KNDy neurons located in the hypothalamic arcuate nucleus (ARC), which are reported to express kisspeptin, Neurokinin B, and dynorphin A, are indispensable for the gonadotropin-releasing hormone (GnRH) pulse generation that results in rhythmic GnRH secretion. The aims of the present study were to investigate the effects of peripheral administration of the Neurokinin 3 Receptor (NK3R/TACR3, a Receptor for Neurokinin B) antagonist, SB223412, on GnRH pulse-generating activity and pulsatile luteinizing hormone (LH) secretion in ovariectomized Shiba goats treated with luteal phase levels of estrogen. The NK3R antagonist was infused intravenously for 4 h {0.16 or 1.6 mg/(kg body weight [BW]·4 h)} during which multiple unit activity (MUA) in the ARC was recorded, an electrophysiological technique commonly employed to monitor GnRH pulse generator activity. In a separate experiment, the NK3R antagonist (40 or 200 mg/[kg BW·day]) was administered orally for 7 days to determine whether the NK3R antagonist could modulate pulsatile LH secretion when administered via the oral route. Intravenous infusion of the NK3R antagonist significantly increased the interval of episodic bursts of MUA compared with that of the controls. Oral administration of the antagonist for 7 days also significantly prolonged the interpulse interval of LH pulses. The results of this study demonstrate that peripheral administration of an NK3R antagonist suppresses pulsatile LH secretion by acting on the GnRH pulse generator, suggesting that NK3R antagonist administration could be used to modulate reproductive functions in ruminants.

  • the efficacy of a newly developed Neurokinin 3 Receptor agonist b21 750 on luteinizing hormone secretion in cycling goats
    Journal of Reproduction and Development, 2019
    Co-Authors: Shinya Oishi, Natsumi Endo, Tomomi Tanaka, Larasati Puji Rahayu, Shinji Kuwai
    Abstract:

    This study aimed to investigate the efficacy of a newly developed NK3 Receptor agonist (B21-750) on the secretion of luteinizing hormone (LH) in association with ovarian steroid hormones during the follicular phase (FP, n = 5) and luteal phase (LP, n = 5) of Shiba goats. The FP group was treated with both prostaglandin F2α and progesterone-controlled internal drug release (CIDR) inserts for 10 d, and B21-750 (200 nmol) was injected 12 h after removing the CIDR. Meanwhile, the LP group received B21-750 injections on a day during the mid-luteal phase. LH secretion increased at 1 h after B21-750 injection in both groups. The percent changes in the area under the curve of LH was higher during the hour after injection than during the hour before injection in both groups. Thus, this study demonstrated that B21-750 induces rapid LH secretion for a short period during both the follicular and luteal phases.

  • SB223412, a Neurokinin-3 Receptor-selective antagonist, suppresses testosterone secretion in male guinea pigs.
    Theriogenology, 2017
    Co-Authors: Sho Nakamura, Shinya Oishi, Koki Yamamoto, Yoshiko Ito, Chudai Takahashi, Mingdao Dai, Miyu Tanahashi, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-ichiro Maeda
    Abstract:

    Guinea pigs are important zoo animals and have been recommended for animal-assisted activities or therapy, however there are problems concerning testosterone inducing aggressive or sexual behaviors in male guinea pigs. Testicular testosterone secretion is regulated by pulsatile gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release in mammals. The mechanism generating GnRH/LH pulses is thought to be governed by kisspeptin neurons, which coexpress Neurokinin B (NKB) and dynorphin A (Dyn), in the arcuate nucleus (ARC). Kisspeptin neurons in the ARC are frequently referred to as KNDy neurons. The purpose of this study was to examine whether the antagonization of NKB-Neurokinin-3 Receptor (NK3R) signaling can manipulate testosterone secretion in male guinea pigs. A single subcutaneous administration or 7 days of oral administration of an NK3R-selective antagonist, SB223412 (50 mg/body), significantly decreased plasma testosterone levels in male guinea pigs. In vitro binding assays confirmed that SB223412 has a high affinity to guinea pig NK3R. These results suggest that SB223412 could be used as an orally-available compound to suppress testosterone levels in male guinea pigs. Double labeling in situ hybridization of kisspeptin and either NKB or Dyn showed that kisspeptin-expressing neurons contained NKB (77.9%) or Dyn (62.3%) in the ARC, suggesting the presence of KNDy neurons in the ARC of guinea pigs. In conclusion, the present study shows that SB223412 could be a candidate compound to suppress testosterone secretion in male guinea pigs for controlling sexual and aggressive behaviors in the species.

  • neuropeptide derivatives to regulate the reproductive axis kisspeptin Receptor kiss1r ligands and Neurokinin 3 Receptor nk3r ligands
    Biopolymers, 2016
    Co-Authors: Shinya Oishi, Nobutaka Fujii
    Abstract:

    Recent research has indicated pivotal roles for neuropeptides and their cognate Receptors in reproductive physiology. Kisspeptins are RF-amide neuropeptides that stimulate gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. Neurokinin B (NKB) is a member of the tachykinin family of neuropeptides and positively regulates pulsatile GnRH secretion. These peptides are coexpressed in kisspeptin/NKB/Dyn (KNDy) neurons of the arcuate nucleus, where they contribute to the regulation of puberty onset and other reproductive functions. In this review, the design of peptide ligands for the kisspeptin (KISS1R) and Neurokinin-3 (NK3R) Receptors are described. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 588–597, 2016.

  • Structure–activity relationship study on senktide for development of novel potent Neurokinin-3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

Naomi E. Rance - One of the best experts on this subject based on the ideXlab platform.

  • Glutamatergic Neurokinin 3 Receptor Neurons in the Median Preoptic Nucleus Modulate Heat-Defense Pathways in Female Mice.
    Endocrinology, 2019
    Co-Authors: Sally J. Krajewski-hall, Nathaniel T. Mcmullen, Filipa Miranda Dos Santos, Elise M. Blackmore, Naomi E. Rance
    Abstract:

    We have proposed that arcuate neurons coexpressing kisspeptin, Neurokinin B, and dynorphin (KNDy neurons) contribute to hot flushes via projections to Neurokinin 3 Receptor (NK3R)-expressing neurons in the median preoptic nucleus (MnPO). To characterize the thermoregulatory role of MnPO NK3R neurons in female mice, we ablated these neurons using injections of saporin toxin conjugated to a selective NK3R agonist. Loss of MnPO NK3R neurons increased the core temperature (TCORE) during the light phase, with the frequency distributions indicating a regulated shift in the balance point. The increase in TCORE in the ablated mice occurred despite changes in the ambient temperature and regardless of estrogen status. We next determined whether an acute increase in ambient temperature or higher TCORE would induce Fos in preoptic enhanced green fluorescent protein (EGFP)-immunoreactive neurons in Tacr3-EGFP mice. Fos activation was increased in the MnPO but no induction of Fos was found in NK3R (EGFP-immunoreactive) neurons. Thus, MnPO NK3R neurons are not activated by warm thermosensors in the skin or viscera and are not warm-sensitive neurons. Finally, RNAscope was used to determine whether Tacr3 (NK3R) mRNA was coexpressed with vesicular glutamate transporter 2 or vesicular γ-aminobutyric acid (GABA) transporter mRNA, markers of glutamatergic and GABAergic neurotransmission, respectively. In the MnPO, 94% of NK3R neurons were glutamatergic, but in the adjacent medial preoptic area, 97% of NK3R neurons were GABAergic. Thus, NK3R neurons in the MnPO are glutamatergic and play a role in reducing TCORE but are not activated by warm thermal stimuli (internal or external). These findings suggest that KNDy neurons modulate thermosensory pathways for heat defense indirectly via a subpopulation of glutamatergic MnPO neurons that express NK3R.

  • Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat.
    Endocrinology, 2015
    Co-Authors: Melinda A. Mittelman-smith, Sally J. Krajewski-hall, Nathaniel T. Mcmullen, Naomi E. Rance
    Abstract:

    KNDy neurons facilitate tail skin vasodilation and modulate the effects of estradiol on thermoregulation. We hypothesize that KNDy neurons influence cutaneous vasodilation via projections to neurons in the median preoptic nucleus (MnPO) that express the Neurokinin 3 Receptor (NK3R). In support of this hypothesis, focal microinjections of senktide, an NK3R agonist, into the MnPO lowers core temperature (TCORE) in the female rat. To further study the role of MnPO NK3R neurons in thermoregulation, these neurons were specifically ablated using a conjugate of a selective NK3R agonist and saporin (NK3-SAP). NK3-SAP or blank-SAP (control) was injected into the MnPO/medial septum. Tail skin temperature (TSKIN) and TCORE were measured in ovariectomized rats exposed to 3 ambient temperatures (TAMBIENT) before and after estradiol-17β (E2) treatment. Before killing, we injected senktide (sc), monitored TCORE for 70 minutes, and harvested brains for Fos immunohistochemistry. Ablation of MnPO NK3R neurons lowered TSKIN...

  • Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat.
    Endocrinology, 2015
    Co-Authors: Melinda A. Mittelman-smith, Sally J. Krajewski-hall, Nathaniel T. Mcmullen, Naomi E. Rance
    Abstract:

    KNDy neurons facilitate tail skin vasodilation and modulate the effects of estradiol on thermoregulation. We hypothesize that KNDy neurons influence cutaneous vasodilation via projections to neurons in the median preoptic nucleus (MnPO) that express the Neurokinin 3 Receptor (NK3R). In support of this hypothesis, focal microinjections of senktide, an NK3R agonist, into the MnPO lowers core temperature (TCORE) in the female rat. To further study the role of MnPO NK3R neurons in thermoregulation, these neurons were specifically ablated using a conjugate of a selective NK3R agonist and saporin (NK3-SAP). NK3-SAP or blank-SAP (control) was injected into the MnPO/medial septum. Tail skin temperature (TSKIN) and TCORE were measured in ovariectomized rats exposed to 3 ambient temperatures (TAMBIENT) before and after estradiol-17β (E2) treatment. Before killing, we injected senktide (sc), monitored TCORE for 70 minutes, and harvested brains for Fos immunohistochemistry. Ablation of MnPO NK3R neurons lowered TSKIN at neutral and subneutral TAMBIENT regardless of E2 treatment. However, ablation did not prevent the effects of E2 on TCORE and TSKIN. In control rats, senktide injections induced hypothermia with numerous Fos-immunoreactive cells in the MnPO. In contrast, in NK3-SAP rats, senktide did not alter TCORE and minimal Fos-immunoreactive neurons were identified in the MnPO. These data show that NK3R neurons in the MnPO are required for the hypothermic effects of senktide but not for the E2 modulation of thermoregulation. The lower TSKIN in NK3-SAP-injected rats suggests that MnPO NK3R neurons, like KNDy neurons, facilitate cutaneous vasodilation, an important heat-dissipation effector.

  • modulation of body temperature and lh secretion by hypothalamic kndy kisspeptin Neurokinin b and dynorphin neurons a novel hypothesis on the mechanism of hot flushes
    Frontiers in Neuroendocrinology, 2013
    Co-Authors: Naomi E. Rance, Penny A Dacks, Melinda A Mittelmansmith, Andrej A Romanovsky, Sally J Krajewskihall
    Abstract:

    Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, Neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the Neurokinin 3 Receptor (NK3R), the primary Receptor for NKB. Furthermore, activation of NK3R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.

  • Activation of Neurokinin 3 Receptors in the median preoptic nucleus decreases core temperature in the rat.
    Endocrinology, 2011
    Co-Authors: Penny A Dacks, Sally J. Krajewski, Naomi E. Rance
    Abstract:

    Estrogens have pronounced effects on thermoregulation, as illustrated by the occurrence of hot flushes secondary to estrogen withdrawal in menopausal women. Because Neurokinin B (NKB) gene expression is markedly increased in the infundibular (arcuate) nucleus of postmenopausal women, and is modulated by estrogen withdrawal and replacement in multiple species, we have hypothesized that NKB neurons could play a role in the generation of flushes. There is no information, however, on whether the primary NKB Receptor [Neurokinin 3 Receptor (NK3R)] modulates body temperature in any species. Here, we determine the effects of microinfusion of a selective NK3R agonist (senktide) into the rat median preoptic nucleus (MnPO), an important site in the heat-defense pathway. Senktide microinfusion into the rat MnPO decreased core temperature in a dose-dependent manner. The hypothermia induced by senktide was similar in ovariectomized rats with and without 17β-estradiol replacement. The hypothermic effect of senktide was...

Ryosuke Misu - One of the best experts on this subject based on the ideXlab platform.

  • Structure–activity relationship study on senktide for development of novel potent Neurokinin-3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

  • structure activity relationship study on senktide for development of novel potent Neurokinin 3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

  • Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura
    Abstract:

    Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the Neurokinin-3 Receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.

  • Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation
    2014
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura
    Abstract:

    Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the Neurokinin-3 Receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity

  • Structure-activity relationship study of tachykinin peptides for the development of novel Neurokinin-3 Receptor selective agonists.
    Bioorganic & Medicinal Chemistry, 2013
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Nobutaka Fujii
    Abstract:

    Neurokinin B (NKB) is a potential regulator of pulsatile gonadotropin-releasing hormone (GnRH) secretion via activation of the Neurokinin-3 Receptor (NK3R). NKB with the consensus sequence of the tachykinin peptide family also binds to other tachykinin Receptors [Neurokinin-1 Receptor (NK1R) and Neurokinin-2 Receptor (NK2R)] with low selectivity. In order to identify the structural requirements for the development of novel potent and selective NK3R agonists, a structure-activity relationship (SAR) study of [MePhe(7)]-NKB and other naturally occurring tachykinin peptides was performed. The substitutions to naturally occurring tachykinins with Asp and MePhe improved the Receptor binding and agonistic activity for NK3R. The corresponding substitutions to NKB provided an NK3R selective analog.

Satoshi Ohkura - One of the best experts on this subject based on the ideXlab platform.

  • A Neurokinin 3 Receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle.
    Biology of Reproduction, 2017
    Co-Authors: Sho Nakamura, Takashi Yamamura, Satoshi Ohkura, Yoshihiro Wakabayashi, Shuichi Matsuyama
    Abstract:

    Abstract Pulsatile gonadotropin-releasing hormone (GnRH) secretion, which is indispensable for follicular development, is suppressed in lactating dairy and beef cattle. Neurokinin B (NKB) neurons in the arcuate nucleus of the hypothalamus are considered to play an essential role in generating the pulsatile mode of GnRH/luteinizing hormone (LH) secretion. The present study aimed to clarify the role of NKB-Neurokinin 3 Receptor (NK3R) signaling in the pulsatile pattern of GnRH/gonadotropin secretion in postpartum lactating cattle. We examined the effects of the administration of an NK3R-selective agonist, senktide, on gonadotropin secretion in lactating cattle. The lactating cattle, at approximately 7 days postpartum, were intravenously infused with senktide (30 or 300 nmol/min) or vehicle for 24 h. The administration of 30 or 300 nmol/min senktide significantly increased LH pulse frequency compared to in the control group during 0-4 or 20-24 h after infusion, respectively. Moreover, LH and follicle-stimulating hormone levels were gradually increased by 300 nmol/min administration of senktide during the 0-4-h sampling period. Ultrasonography of the ovaries was performed to identify the first postpartum ovulation in senktide-administered lactating cattle. The interval from calving to first postpartum ovulation was significantly shorter in the 300 nmol/min senktide-administered group than in the control group. Taken together, these findings suggest that senktide infusion elicits an increase in LH pulse frequency that may stimulate follicular development and, in turn, induce the first postpartum ovulation in lactating cattle.

  • Structure–activity relationship study on senktide for development of novel potent Neurokinin-3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

  • structure activity relationship study on senktide for development of novel potent Neurokinin 3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

  • Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura
    Abstract:

    Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the Neurokinin-3 Receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.

  • Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation
    2014
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura
    Abstract:

    Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the Neurokinin-3 Receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity

Takashi Yamamura - One of the best experts on this subject based on the ideXlab platform.

  • A Neurokinin 3 Receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle.
    Biology of Reproduction, 2017
    Co-Authors: Sho Nakamura, Takashi Yamamura, Satoshi Ohkura, Yoshihiro Wakabayashi, Shuichi Matsuyama
    Abstract:

    Abstract Pulsatile gonadotropin-releasing hormone (GnRH) secretion, which is indispensable for follicular development, is suppressed in lactating dairy and beef cattle. Neurokinin B (NKB) neurons in the arcuate nucleus of the hypothalamus are considered to play an essential role in generating the pulsatile mode of GnRH/luteinizing hormone (LH) secretion. The present study aimed to clarify the role of NKB-Neurokinin 3 Receptor (NK3R) signaling in the pulsatile pattern of GnRH/gonadotropin secretion in postpartum lactating cattle. We examined the effects of the administration of an NK3R-selective agonist, senktide, on gonadotropin secretion in lactating cattle. The lactating cattle, at approximately 7 days postpartum, were intravenously infused with senktide (30 or 300 nmol/min) or vehicle for 24 h. The administration of 30 or 300 nmol/min senktide significantly increased LH pulse frequency compared to in the control group during 0-4 or 20-24 h after infusion, respectively. Moreover, LH and follicle-stimulating hormone levels were gradually increased by 300 nmol/min administration of senktide during the 0-4-h sampling period. Ultrasonography of the ovaries was performed to identify the first postpartum ovulation in senktide-administered lactating cattle. The interval from calving to first postpartum ovulation was significantly shorter in the 300 nmol/min senktide-administered group than in the control group. Taken together, these findings suggest that senktide infusion elicits an increase in LH pulse frequency that may stimulate follicular development and, in turn, induce the first postpartum ovulation in lactating cattle.

  • Structure–activity relationship study on senktide for development of novel potent Neurokinin-3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

  • structure activity relationship study on senktide for development of novel potent Neurokinin 3 Receptor selective agonists
    MedChemComm, 2015
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura, Shinya Oishi
    Abstract:

    Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate Neurokinin-3 Receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased Receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.

  • Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura
    Abstract:

    Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the Neurokinin-3 Receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.

  • Development of Novel Neurokinin 3 Receptor (NK3R) Selective Agonists with Resistance to Proteolytic Degradation
    2014
    Co-Authors: Ryosuke Misu, Taro Noguchi, Hiroaki Ohno, Shinya Oishi, Ai Yamada, Takashi Yamamura, Fuko Matsuda, Koki Yamamoto, Hiroaki Okamura, Satoshi Ohkura
    Abstract:

    Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the Neurokinin-3 Receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity