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Shinji Kageyama - One of the best experts on this subject based on the ideXlab platform.
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determination of Growth Hormone Secretagogue pralmorelin ghrp 2 and its metabolite in human urine by liquid chromatography electrospray ionization tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Masato Okano, Ayako Ikekita, Mitsuhiko Sato, Shinji KageyamaAbstract:GHRP-2 (pralmorelin, D-Ala-D-(β-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH2), which belongs to a class of Growth Hormone Secretagogue (GHS), is intravenously used to diagnose Growth Hormone (GH) deficiency. Because it may be misused in expectation of a Growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(β-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5–10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6–3.8% (intra-day) and 1.9–4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine. Copyright © 2010 John Wiley & Sons, Ltd.
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determination of Growth Hormone Secretagogue pralmorelin ghrp 2 and its metabolite in human urine by liquid chromatography electrospray ionization tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Masato Okano, Ayako Ikekita, Mitsuhiko Sato, Shinji KageyamaAbstract:GHRP-2 (pralmorelin, D-Ala-D-(beta-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH(2)), which belongs to a class of Growth Hormone Secretagogue (GHS), is intravenously used to diagnose Growth Hormone (GH) deficiency. Because it may be misused in expectation of a Growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(beta-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5-10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6-3.8% (intra-day) and 1.9-4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine.
Masato Okano - One of the best experts on this subject based on the ideXlab platform.
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determination of Growth Hormone Secretagogue pralmorelin ghrp 2 and its metabolite in human urine by liquid chromatography electrospray ionization tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Masato Okano, Ayako Ikekita, Mitsuhiko Sato, Shinji KageyamaAbstract:GHRP-2 (pralmorelin, D-Ala-D-(β-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH2), which belongs to a class of Growth Hormone Secretagogue (GHS), is intravenously used to diagnose Growth Hormone (GH) deficiency. Because it may be misused in expectation of a Growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(β-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5–10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6–3.8% (intra-day) and 1.9–4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine. Copyright © 2010 John Wiley & Sons, Ltd.
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determination of Growth Hormone Secretagogue pralmorelin ghrp 2 and its metabolite in human urine by liquid chromatography electrospray ionization tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Masato Okano, Ayako Ikekita, Mitsuhiko Sato, Shinji KageyamaAbstract:GHRP-2 (pralmorelin, D-Ala-D-(beta-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH(2)), which belongs to a class of Growth Hormone Secretagogue (GHS), is intravenously used to diagnose Growth Hormone (GH) deficiency. Because it may be misused in expectation of a Growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(beta-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5-10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6-3.8% (intra-day) and 1.9-4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine.
William D. Lubell - One of the best experts on this subject based on the ideXlab platform.
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Azapeptide analogues of the Growth Hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the Growth Hormone Secretagogue receptor 1a.
Journal of Medicinal Chemistry, 2012Co-Authors: Caroline Proulx, Emilie Picard, Damien Boeglin, Petra Pohankova, Sylvain Chemtob, William D. LubellAbstract:The synthetic hexapeptide Growth Hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the Growth Hormone Secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the d-Trp2, Ala3, or Trp4 position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the d-Trp2 residue proved important for CD36 receptor affinity; however, His1 could be replaced by Ala1 without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr4]-GHRP-6 (15), [Ala1, azaPhe2]-GHRP-6 (16), and [azaLeu3, Ala6]-GHRP-6 ...
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azapeptide analogues of the Growth Hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the Growth Hormone Secretagogue receptor 1a
Journal of Medicinal Chemistry, 2012Co-Authors: Caroline Proulx, Emilie Picard, Damien Boeglin, Petra Pohankova, Sylvain Chemtob, Huy Ong, William D. LubellAbstract:The synthetic hexapeptide Growth Hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the Growth Hormone Secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the D-Trp(2), Ala(3), or Trp(4) position gave aza-GHRP-6 analogues with reduced affinity toward the GHS-R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the D-Trp(2) residue proved important for CD36 receptor affinity; however, His(1) could be replaced by Ala(1) without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr(4)]-GHRP-6 (15), [Ala(1), azaPhe(2)]-GHRP-6 (16), and [azaLeu(3), Ala(6)]-GHRP-6 (33) all exhibited antiangiogenic activity.
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structure activity analysis of the Growth Hormone Secretagogue ghrp 6 by alpha and beta amino gamma lactam positional scanning
Chemical Biology & Drug Design, 2010Co-Authors: Nicolas Boutard, Andrew G Jamieson, Huy Ong, William D. LubellAbstract:Incorporation of amino lactams into biologically active peptides restricts conformational mobility and may enhance selectivity and increase potency. α- and β-amino γ-lactams (Agl and Bgl), in both S and R configurations, were introduced into the Growth Hormone Secretagogue GHRP-6 using a Fmoc-compatible solid-phase protocol relying on N-alkylation with five- and six-membered cyclic sulfamidates, followed by lactam annulation under microwave heating. Using this protocol in conjunction with IRORI KanTM techniques furnished eleven new GHRP-6 analogs, and their binding affinity IC50 values on both the Growth Hormone Secretagogue receptor 1a (GHS-R1a) and CD36 receptors are herein reported. The results indicate that selectivity towards one receptor or the other can be modulated by lactam substitution, typically at the Ala3 and the d-Phe5 positions.
Roy G Smith - One of the best experts on this subject based on the ideXlab platform.
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ghrelin stimulation of Growth Hormone release and appetite is mediated through the Growth Hormone Secretagogue receptor
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Yuxiang Sun, Pei Wang, Hui Zheng, Roy G SmithAbstract:Abstract Synthetic agonists of the Growth Hormone Secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this Hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fasting-induced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like Growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like Growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on Growth or appetite.
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agonist specific coupling of Growth Hormone Secretagogue receptor type 1a to different intracellular signaling systems role of adenosine
Neuroendocrinology, 2004Co-Authors: Marcos C Carreira, Roy G Smith, Jesus P Camina, Felipe F CasanuevaAbstract:The Growth Hormone Secretagogue receptor subtype 1a (GHSR-1a) is involved in biological actions of ghrelin by triggering intracellular second messengers coupled to heterotrimeric G-protein complex inv
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Growth Hormone Secretagogue receptor family members and ligands
Endocrine, 2001Co-Authors: Roy G Smith, Oksana C Palyha, Scott D Feighner, Patrick R Griffin, Shengshung Pong, Karen K Mckee, Reid J Leonard, Alex R T Bailey, Carina P Tan, Andrew D. HowardAbstract:We have previously reported the cloning and characterization of a new orphan G-protein-coupled receptor (GPC-R), the Growth Hormone Secretagogue receptor (GHS-R), and shown that this receptor mediates the activity of the Growth Hormone-releasing peptides (GHRPs) and nonpeptide ligands such as L-692,429 and MK-0677. Because the GHS-R obviously does not belong to any of the known GPC-R subfamilies, we searched for GHS-R family members by screening a human genomic library using low-stringency hybridization and screening a Pufferfish genomic library. The Pufferfish was selected because of its compact genome. From the human genomic library, a homolog, GPR 38, with 52% identity to the GHS-R was isolated. From the Pufferfish library, three family members were isolated. The Pufferfish gene having 58% identity to the GHS-R, on expression in HEK293 cells, was activated with GHRP-6 and MK-0677. These results indicate that the GHS-R has been conserved for at least 400 million years and that the Pufferfish genome is appropriate for isolation of GHS-R family members. In our search for endogenous ligands for the orphan receptors GHS-R and GPR38, we showed that adenosine is a partial agonist of the GHS-R and that motilin is the endogenous ligand for GPR38. We also confirmed that the endogenous ligand ghrelin is a full agonist of the GHS-R.
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adenosine a partial agonist of the Growth Hormone Secretagogue receptor
Biochemical and Biophysical Research Communications, 2000Co-Authors: Scott D Feighner, Roy G Smith, Patrick R Griffin, Yuan Xu, Alexander G A Smith, Jimmy Calacay, C S Pong, Denis Leong, Anna PomesAbstract:Abstract The Growth Hormone Secretagogue receptor (GHS-R) is involved in the regulation of pulsatile GH release. However, until recently, natural endogenous ligands for the receptor were unknown. We fractionated porcine hypothalamic extracts and assayed fractions for activity on HEK293 cells expressing GHS-R and aequorin. A partial agonist was isolated and identified using microspray tandem mass spectrometry as adenosine. GHS-R activation by adenosine and synthetic adenosine agonists is inhibited by the GHS-R selective antagonists L-765,867, D-Lys 3 -GHRP-6, and by theophylline and XAC. Cross desensitization of the GHS-R occurs with both MK-0677 and adenosine. Ligand binding and site directed mutagenesis studies show that adenosine binds to a binding site that is distinct from the previously characterized MK-0677 and GHRP-6 binding pocket. We propose, that adenosine is a physiologically important endogenous GHS-R ligand and speculate that GHS-R ligands modulate dopamine release from hypothalamic neurons.
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cloning and characterization of two human g protein coupled receptor genes gpr38 and gpr39 related to the Growth Hormone Secretagogue and neurotensin receptors
Genomics, 1997Co-Authors: Karen Kulju Mckee, Oksana C Palyha, Scott D Feighner, Donna L Hreniuk, Roy G Smith, Andrew D. Howard, Lex H T Van Der PloegAbstract:Abstract The recent cloning of a Growth Hormone Secretagogue receptor (GHS-R) from human pituitary gland and brain identified a third G protein-coupled receptor (GPC-R) involved in the control of Growth Hormone release. The nucleotide sequence of the GHS-R is most closely related to the neurotensin receptor-1 (NT-R1) (35% overall protein identity). Two human GPC-Rs related to both the type 1a GHS-R and NT-Rs were cloned and characterized. Hybridization at low posthybridizational stringency with restriction enzyme-digested human genomic DNA resulted in the identification of a genomic clone encoding a first GHS-R/NT-R family member (GPR38). A cDNA clone was identified encoding a second GHS-R-related gene (GPR39). GPR38 and GPR39 share significant amino acid sequence identity with the GHS-R and NT-Rs 1 and 2. An acidic residue (E124) in TM-3, essential for the binding and activation of the GHS-R by structurally dissimilar GHSs, was conserved in GPR38 and GPR39. GPR38 is encoded by a single gene expressed in thyroid gland, stomach, and bone marrow. GPR39 is encoded by a highly conserved single-copy gene, expressed in brain and other peripheral tissues. Fluorescence in situ hybridization localized the genes for GPR38 and GPR39 to separate chromosomes, distinct from the gene encoding the GHS-R and NT-R type 1. The ligand-binding and functional properties of GPR38 and GPR39 remain to be determined.
Mitsuhiko Sato - One of the best experts on this subject based on the ideXlab platform.
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determination of Growth Hormone Secretagogue pralmorelin ghrp 2 and its metabolite in human urine by liquid chromatography electrospray ionization tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Masato Okano, Ayako Ikekita, Mitsuhiko Sato, Shinji KageyamaAbstract:GHRP-2 (pralmorelin, D-Ala-D-(β-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH2), which belongs to a class of Growth Hormone Secretagogue (GHS), is intravenously used to diagnose Growth Hormone (GH) deficiency. Because it may be misused in expectation of a Growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(β-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5–10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6–3.8% (intra-day) and 1.9–4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine. Copyright © 2010 John Wiley & Sons, Ltd.
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determination of Growth Hormone Secretagogue pralmorelin ghrp 2 and its metabolite in human urine by liquid chromatography electrospray ionization tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Masato Okano, Ayako Ikekita, Mitsuhiko Sato, Shinji KageyamaAbstract:GHRP-2 (pralmorelin, D-Ala-D-(beta-naphthyl)-Ala-Ala-Trp-D-Phe-Lys-NH(2)), which belongs to a class of Growth Hormone Secretagogue (GHS), is intravenously used to diagnose Growth Hormone (GH) deficiency. Because it may be misused in expectation of a Growth-promoting effect by athletes, the illicit use of GHS by athletes has been prohibited by the World Anti-Doping Agency (WADA). Therefore, the mass spectrometric identification of urinary GHRP-2 and its metabolite D-Ala-D-(beta-naphthyl)-Ala-Ala-OH (AA-3) was studied using liquid chromatography/electrospray ionization tandem mass spectrometry for doping control purposes. The method consists of solid-phase extraction using stable-isotope-labeled GHRP-2 as an internal standard and subsequent ultra-performance liquid chromatography/tandem mass spectrometry, and the two target peptides were determined at urinary concentrations of 0.5-10 ng/mL. The recoveries ranged from 84 to 101%, and the assay precisions were calculated as 1.6-3.8% (intra-day) and 1.9-4.3% (inter-day). Intravenous administration of GHRP-2 in ten male volunteers was studied to demonstrate the applicability of the method. In all ten cases, unchanged GHRP-2 and its specific metabolite AA-3 were detected in urine.
