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Hisanori Matsui - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide kiss1 receptor kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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differential changes in luteinizing hormone secretion after administration of the investigational Metastin kisspeptin analog tak 683 in goats
Animal Reproduction Science, 2015Co-Authors: Natsumi Endo, Hisanori Matsui, Satoshi Ohkura, Chie Tamesaki, Yoshihiro Wakabayashi, Akira Tanaka, Tatsuya Watanabe, Hiroaki Okamura, Tomomi TanakaAbstract:Abstract This study aimed to evaluate the hormonal and ovarian responses to the administration of a Metastin/kisspeptin analog (TAK-683) under the endocrine environments of luteal and follicular phases in goats. Five estrous cycling goats received a prostaglandin F2α injection followed by 10 days of progesterone treatment by CIDR. The TAK-683 (35 nmol) was intravenously administered (Hour 0) on 3 days after CIDR insertion (luteal phase condition; LC) and at 12 h after CIDR removal (follicular phase condition; FC). Blood samples were collected at 10 min (−2 to 6 h), 2 h (6–24 h) or 6 h intervals (24–48 h). In the LC, small increases in the basal concentrations of LH were observed after TAK-683 administration from 0 to 6 h, which were associated with an increase in estradiol concentration, followed by a surge-like release of LH with a peak at 12.5 ± 1.0 h (n = 4) after TAK-683 administration. In the FC, a surge-like release of LH occurred immediately after TAK-683 administration with a peak at 6.0 ± 3.5 h (n = 5), which was earlier than that in the LC (P
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ovarian and hormonal responses to follicular phase administration of investigational Metastin kisspeptin analog tak 683 in goats
Reproduction in Domestic Animals, 2014Co-Authors: Y Goto, Hisanori Matsui, Satoshi Ohkura, Natsumi Endo, Yoshihiro Wakabayashi, Akira Tanaka, Hiroaki Okamura, Kiyosuke Nagai, Masami Kusaka, Tomomi TanakaAbstract:This study evaluated the effects of follicular phase administration of TAK-683, an investigational Metastin/kisspeptin analog, on follicular growth, ovulation, luteal function and reproductive hormones in goats. After confirmation of ovulation by transrectal ultrasonography (Day 0), PGF2α (2 mg/head of dinoprost) was administered intramuscularly on Day 10 to induce luteal regression. At 12 h after PGF2α administration, intravenous administration of vehicle or 35 nmol (50 μg)/head of TAK-683 was performed in control (n = 4) and treatment (n = 4) groups, respectively. Blood samples were collected at 6-h intervals for 96 h and then daily until the detection of subsequent ovulation (second ovulation). After the second ovulation, ultrasound examinations and blood sampling were performed every other day or daily until the subsequent ovulation (third ovulation). Mean concentrations of LH and FSH in the treatment group were significantly higher 6 h after TAK-683 treatment than those in the control group (12.0 ± 10.7 vs 1.0 ± 0.7 ng/ml for LH, 47.5 ± 28.2 vs 15.1 ± 3.4 ng/ml for FSH, p < 0.05), whereas mean concentrations of oestradiol in the treatment group decreased immediately after treatment (p < 0.05) as compared with the control group. Ovulation tended to be delayed (n = 2) or occurred early (n = 1) in the treatment group as compared with the control group. For the second ovulation, ovulatory follicles in the treatment group were significantly smaller in maximal diameter than in the control group (3.8 ± 0.5 vs 5.4 ± 0.2 mm, p < 0.05, n = 3). Administration of TAK-683 in the follicular phase stimulates gonadotropin secretion and may have resulted in ovulation of premature follicles in goats.
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Physicochemically and Pharmacokinetically Stable Nonapeptide KISS1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of Metastin(45–54) produced peptide analogues with higher metabolic stability than Metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]Metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than Metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]Metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than Metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]Metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
Yoshihiro Takatsu - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide kiss1 receptor kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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Physicochemically and Pharmacokinetically Stable Nonapeptide KISS1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of Metastin(45–54) produced peptide analogues with higher metabolic stability than Metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]Metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than Metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]Metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than Metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]Metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
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involvement of anteroventral periventricular Metastin kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats
Journal of Reproduction and Development, 2007Co-Authors: Sachika Adachi, Yoshihiro Takatsu, Tetsuya Ohtaki, Shunji Yamada, Mika Kinoshita, Hisanori Matsui, Hitomi Sugiura, Hirokazu MatsumotoAbstract:Metastin/kisspeptin, the KiSS-1 gene product, has been identified as an endogenous ligand of GPR54 that reportedly regulates GnRH/LH surges and estrous cyclicity in female rats. The aim of the present study was to determine if Metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges. We demonstrated that preoptic area (POA) infusion of the anti-rat Metastin/kisspeptin monoclonal antibody blocked the estrogen-induced LH surge, indicating that endogenous Metastin/kisspeptin released around the POA mediates the estrogen positive feedback effect on GnRH/LH release. Metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) may be responsible for mediating the feedback effect because the percentage of c-Fos-expressing KiSS-1 mRNA-positive cells to total KiSS-1 mRNA-positive cells was significantly higher in the afternoon than in the morning in the anteroventral periventricular nucleus (AVPV) of high estradiol (E2)-treated females. The percentage of c-Fos-expressing Metastin/kisspeptin neurons was not different between the afternoon and morning in the arcuate nucleus (ARC). Most of the KiSS-1 mRNA expressing cells contain ERα immunoreactivity in the AVPV and ARC. In addition, AVPV KiSS-1 mRNA expressions were highest in the proestrous afternoon and lowest in the diestrus 1 in females and were increased by estrogen treatment in ovariectomized animals. On the other hand, the ARC KiSS-1 mRNA expressions were highest at diestrus 2 and lowest at proestrous afternoon and were increased by ovariectomy and decreased by high estrogen treatment. Males lacking the surge mode of GnRH/LH release showed no obvious cluster of Metastin/kisspeptin-immunoreactive neurons in the AVPV when compared with high E2-treated females, which showed a much greater density of these neurons. Taken together, the present study demonstrates that the AVPV Metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges in female rats.
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peripheral administration of Metastin induces marked gonadotropin release and ovulation in the rat
Biochemical and Biophysical Research Communications, 2004Co-Authors: Hisanori Matsui, Yoshihiro Takatsu, Satoshi Kumano, Hirokazu Matsumoto, Tetsuya OhtakiAbstract:Metastin is a novel peptide that has been isolated from the human placenta as the cognate ligand of the G-protein-coupled receptor OT7T175 (or GPR54). However, its physiological functions have not yet been fully investigated. In the present study, we show that subcutaneous administration of Metastin increased the plasma levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone) and induced ovulation in prepubertal female rats that had been pretreated with pregnant mare serum gonadotropin to induce follicle maturation. Furthermore, Metastin administration drastically increased the plasma levels of gonadotropins in male rats. This action was abolished by pretreatment with a GnRH antagonist, and was accompanied by induction of c-Fos immunoreactivity in GnRH neurons. These results suggest that s.c. administered Metastin induces the release of gonadotropin via activation of the hypothalamic GnRH neurons.
Naoki Nishizawa - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide kiss1 receptor kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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Physicochemically and Pharmacokinetically Stable Nonapeptide KISS1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of Metastin(45–54) produced peptide analogues with higher metabolic stability than Metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]Metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than Metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]Metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than Metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]Metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
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design synthesis and biological evaluation of novel investigational nonapeptide kiss1r agonists with testosterone suppressive activity
Journal of Medicinal Chemistry, 2013Co-Authors: Taiji Asami, Kimiko Nishibori, Yasuko Horikoshi, Yoshihiro Ishibashi, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Shin-ichi Matsumoto, Naoki Tarui, Masashi YamaguchiAbstract:Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, Metastin(45–54), possesses a 10-fold higher receptor-binding affinity than full-length Metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [d-Tyr45,d-Trp47,azaGly51,Arg(Me)53]Metastin(45–54) with improved serum stability compared with Metastin(45–54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45–47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]Metastin(46–54), compound 26, which displayed KISS1R binding affinities comparable to Metastin(45–54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length Metastin analog to possess testosterone suppressive activit...
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Design, Synthesis, and Biological Evaluation of Novel Investigational Nonapeptide KISS1R Agonists with Testosterone-Suppressive Activity
2013Co-Authors: Taiji Asami, Kimiko Nishibori, Yasuko Horikoshi, Yoshihiro Ishibashi, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Shin-ichi Matsumoto, Naoki Tarui, Masashi YamaguchiAbstract:Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, Metastin(45–54), possesses a 10-fold higher receptor-binding affinity than full-length Metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [d-Tyr45,d-Trp47,azaGly51,Arg(Me)53]Metastin(45–54) with improved serum stability compared with Metastin(45–54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45–47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]Metastin(46–54), compound 26, which displayed KISS1R binding affinities comparable to Metastin(45–54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length Metastin analog to possess testosterone suppressive activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer
Satoshi Kumano - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide kiss1 receptor kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of Metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of Metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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peripheral administration of Metastin induces marked gonadotropin release and ovulation in the rat
Biochemical and Biophysical Research Communications, 2004Co-Authors: Hisanori Matsui, Yoshihiro Takatsu, Satoshi Kumano, Hirokazu Matsumoto, Tetsuya OhtakiAbstract:Metastin is a novel peptide that has been isolated from the human placenta as the cognate ligand of the G-protein-coupled receptor OT7T175 (or GPR54). However, its physiological functions have not yet been fully investigated. In the present study, we show that subcutaneous administration of Metastin increased the plasma levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone) and induced ovulation in prepubertal female rats that had been pretreated with pregnant mare serum gonadotropin to induce follicle maturation. Furthermore, Metastin administration drastically increased the plasma levels of gonadotropins in male rats. This action was abolished by pretreatment with a GnRH antagonist, and was accompanied by induction of c-Fos immunoreactivity in GnRH neurons. These results suggest that s.c. administered Metastin induces the release of gonadotropin via activation of the hypothalamic GnRH neurons.
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expression of kiss 1 a metastasis suppressor gene in trophoblast giant cells of the rat placenta
Biochimica et Biophysica Acta, 2004Co-Authors: Yasuko Terao, Yoshihiro Takatsu, Satoshi Kumano, Tetsuya Ohtaki, Masahiko Hattori, Atsushi Nishimura, Yasushi ShintaniAbstract:Metastin is encoded by a putative human metastasis suppressor gene KiSS-1, and is the cognate ligand of a G-protein-coupled receptor designated OT7T175. To study the physiological function(s) of Metastin, we cloned rat and mouse KiSS-1 cDNAs both encoding 130-amino acid KiSS-1 proteins. Sequence analysis suggested that processing of the rat and mouse KiSS-1 proteins produces 52-amino-acid peptides, each with an amidated carboxyl terminal and with a single possible disulfide bond, corresponding to rat and mouse Metastins. The carboxyl-terminal sequence of Metastin, known to be essential for functional receptor interaction, was found to be highly conserved among humans and rodents. Real-time PCR analysis indicated that rat KiSS-1 mRNA showed the highest expression level in the cecum and colon. Since KiSS-1 mRNA and Metastin are known to be abundant in human placenta, we further studied the localization of KiSS-1 and OT7T175 mRNAs in rat placenta by in situ hybridization. KiSS-1 and OT7T175 mRNAs were specifically detected in trophoblast giant cells at embryonic day 12.5, and the transcripts in the cells gradually decreased during placental maturation. These results suggest that Metastin/OT7T175 signaling may participate in implantation of the mammalian embryo, placenta formation, and maintenance of pregnancy.
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metastasis suppressor gene kiss 1 encodes peptide ligand of a g protein coupled receptor
Nature, 2001Co-Authors: Tetsuya Ohtaki, Yoshihiro Takatsu, Yasuko Terao, Satoshi Kumano, Yasushi Shintani, Akira Hori, Kimiko Kanehashi, Hirokazu Matsumoto, Susumu Honda, Yasushi MasudaAbstract:Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene1, that suppresses metastases of human melanomas2 and breast carcinomas3 without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named ‘Metastin’. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.
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safety evaluation of kp 10 Metastin 45 54 following once daily intravenous administration for 14 days in dog
International Journal of Toxicology, 2021Co-Authors: Pramod S Terse, James O Peggins, Stephanie B. SeminaraAbstract:Kisspeptin-10 (previously referred as Metastin 45–54), an active fragment of the endogenous full-length kisspeptin-145, is a potential therapeutic agent for reproductive disorders such as infertili...
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G Protein-Coupled Receptor 54-Induced Gonadotropin- Releasing Hormone Release Monitored Indirectly in the Juvenile Male Rhesus Monkey (Macaca mulatta): A Finding with Therapeutic Implications
2013Co-Authors: Stephanie B. Seminara, William F Crowley, Meloni J Dipietro, Suresh Ramaswamy, Tony M PlantAbstract:The effect of continuous administration of the C-terminal fragment of Metastin, the ligand for the G protein-coupled receptor, GPR54, on GnRH-induced LH secretion was examined in three agonadal, juvenile male monkeys whose responsiveness to GnRH was heightened by pretreatment with a chronic pulsatile iv infusion of synthetic GnRH. After bolus injection of 10 �g human (hu) Metastin 45–54 (equivalent to kisspeptin 112–121), the GPR54 agonist was infused continuously at a dose of 100 �g/h and elicited a brisk LH response for approximately 3 h. This rise was then followed by a precipitous drop in LH despite continuous exposure of GPR54 to Metastin 45–54. On d 4, during the final 3hoftheinfusion, single boluses of hu Metastin 45–54 (10 �g), N-methyl-DL-aspartic acid (NMDA) (10 mg/kg) and GnRH (0.3 �g) were administered to interrogate each element of the Metastin
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lc ms ms quantification of a neuropeptide fragment kisspeptin 10 nsc 741805 and characterization of its decomposition product and pharmacokinetics in rats
Journal of Chromatography B, 2013Co-Authors: Zhongfa Liu, Stephanie B. Seminara, Chen Ren, William P Jones, Ping Chen, Yeeming Chan, Nicola Smith, Joseph M CoveyAbstract:The kisspeptins are critical regulators of mammalian reproduction. Kisspeptin-10 ((45)YNWNSFGLRF-NH2(54), kisspeptin-112-121 or Metastin 45-54, NSC 741805), an active fragment of kisspeptin, has been shown to be a potent stimulator of gonadotropin-releasing hormone and secretion of luteinizing hormone in both rodents and primates. This shorter peptide fragment may have clinical utility potential and it is important to characterize its pharmacokinetic property. Recently, the pharmacokinetics of both kisspeptin-54 and kisspeptin-10 were characterized in humans using a radioimmunoassay (RIA), which measures only the immunoreactive kisspeptin (kisspeptin-IR). In this study, a highly sensitive and specific LC-MS/MS assay was developed to quantify kisspeptin-10 levels in rat plasma. The lower limit of quantitation (LLOQ) was 0.5 ng/mL, the within-day and between-day coefficient of variations (CVs) ranged from 5.2 to 15.4% and 1.3 to 14.2%, and the accuracy values ranged from 98 to 114% and 99 to 105%, respectively. With this method, stability studies demonstrated that kisspeptin-10 degraded rapidly with decomposition half-lives of 6.8 min, 2.9 min and 1.7 min at 4 °C, 25 °C, and 37 °C, respectively. The principal decomposition product was characterized as the N-terminal tyrosine deleted kisspeptin-10 (46)NWDSFGLRF-NH2(54). Pharmacokinetic study in rats showed that low ng/mL kisspeptin-10 was detected in the first few minutes, and eliminated rapidly and became undetectable 30 min after intravenous (i.v.) bolus administration of 1.0 mg/kg kisspeptin-10.
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kiss1 mice exhibit more variable hypogonadism than gpr54 mice
Endocrinology, 2007Co-Authors: Yeeming Chan, Risto Lapatto, Carl J Pallais, Dongsheng Zhang, Amy Mahan, Felecia Cerrato, Gloria E Hoffman, Stephanie B. SeminaraAbstract:The G protein-coupled receptor Gpr54 and its ligand Metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse Metastin 43-52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.
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effect of continuous intravenous administration of human Metastin 45 54 on the neuroendocrine activity of the hypothalamic pituitary testicular axis in the adult male rhesus monkey macaca mulatta
Endocrinology, 2007Co-Authors: Suresh Ramaswamy, Stephanie B. Seminara, William F Crowley, Meloni J Dipietro, C R Pohl, Tony M PlantAbstract:In agonadal juvenile male monkeys, continuous administration of human Metastin 45–54 (hu Metastin 45–54) leads to desensitization of its receptor, G protein-coupled receptor 54 (GPR54), and decreased LH. The present study extended this observation to the adult male monkey, a more preclinically relevant model in which robust activity in the hypothalamic-pituitary-testicular axis is present. Continuous iv infusion of hu Metastin 45–54 at either 200 or 400 g/h elicited a marked rise in circulating LH that peaked 2–3 h after initiation of treatment. Thereafter, levels declined, and by 24 h, LH in Metastin 45–54-infused animals was similar to control. LH release in response to an iv bolus of hu Metastin 45–54 (10–30 g) during the fina l3ho fcontinuous infusion was truncated or abolished (low and high peptide dose, respectively). GPR54 desensitization by the high-dose Metastin 45–54 infusion was associated with compromised pituitary response to a bolus GnRH injection (0.3 g). LH pulse amplitude and pulse frequency were markedly suppressed during high-dose Metastin 45–54 treatment. Surprisingly, the fidelity of the relationship between circulating testosterone (T) and LH was distorted during the highdosepeptideinfusion.Thus,foragivenconcentrationofLH, T levels were invariably higher during the high-dose Metastin 45–54 infusion than during vehicle, suggesting that the peptide may exert direct actions on the testis to amplify T production. These findings support the notion that GPR54 is desensitized by continuous exposure to ligand, and they raise the possibility of an intratesticular role of GPR54. (Endocrinology 148: 3364–3370, 2007)