The Experts below are selected from a list of 7551 Experts worldwide ranked by ideXlab platform
Roy G Smith - One of the best experts on this subject based on the ideXlab platform.
-
potent 3 spiropiperidine growth hormone Secretagogues
ChemInform, 2010Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Kang Cheng, Roy G Smith, Klaus D. Schleim, Tom Jacks, Wanda Chan, Arthur A. PatchettAbstract:Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone Secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford Secretagogues with low nanomolar in vitro activity.
-
synthesis and biological activities of spiroheterocyclic growth hormone Secretagogues
ChemInform, 1999Co-Authors: Menghsin Chen, Wanda W.-s. Chan, Arthur A. Patchett, Kang Cheng, Liente Wei, Bridget Butler, Tom Jacks, Patrick P Pollard, Roy G SmithAbstract:The synthesis and biological activities of a series of spiroheterocyclic growth hormone Secretagogues are reported. Modification of the spiroindane part-structure of the prototypal Secretagogue L-162,752 revealed that the spiroindane could be replaced with spirobenzodihydrothiophen derivatives to enhance not only in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4-cyclohexylbutanoic analogs (8a-8d) were also identified to be active Secretagogues.
-
chronic central infusion of growth hormone Secretagogues effects on fos expression and peptide gene expression in the rat arcuate nucleus
Neuroendocrinology, 1999Co-Authors: Alex R T Bailey, Roy G Smith, Gareth Leng, Michelle E Giles, Colin H Brown, Philip M Bull, Lynn P Macdonald, Lynsey C Smith, Suzanne L DicksonAbstract:Growth hormone (GH) Secretagogues induce GH release, in part, by direct actions upon anterior pituitary somatotropes and, in part, by actions upon the neuroendocrine circuitry that regulates GH secretion. In particular, acute systemic administration of GH Secretagogues results in increased neuronal activity and Fos protein expression in the arcuate nucleus of the hypothalamus. Prolonged administration of GH Secretagogues has been reported to have long-lasting effects upon GH release, promoting increased pulsatile secretion. Here, we investigated how chronic central infusion of GH Secretagogues affects the response of arcuate nucleus neurons to acute systemic administration of GH Secretagogues. In male rats, after central infusion of GH Secretagogues for 5 days, there was no sustained expression of Fos in the arcuate nucleus, no significant induction of Fos expression in response to acute GH Secretagogue challenge, and a greatly attenuated secretion of GH in response to acute GH Secretagogue challenge, all reflecting loss of funtional responsiveness to GH Secretagogues. In situ hybridisation revealed that, in the arcuate nucleus of GH Secretagogue-infused rats, mRNA levels for GH-releasing hormone, neuropeptide Y and somatostatin were not different than in saline-infused animals. However, somatostatin mRNA levels in the periventricular nuclei of GH Secretagogue-infused rats were significantly higher than those of saline-infused rats, indicating that this nucleus may play an important role in mediating the effects of chronic GH Secretagogue administration.
-
Tripeptide growth hormone Secretagogues
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Wanda W.-s. Chan, Ravi P Nargund, Kang Cheng, Roy G Smith, Khaled Barakat, Arthur A. PatchettAbstract:Abstract A series of C-terminus capped dipeptides and tripeptides was synthesized as growth hormone (GH) Secretagogues. Among them, tripeptide Aib-D-Trp-D-homoPhe-OEt showed low nanomolar activity in the rat pituitary assay. Thus, we have demonstrated that the GH Secretagogue activity of the hexa- hepta-GH releasing peptides can be mimicked at the tripeptide level.
-
peptidomimetic regulation of growth hormone secretion
Endocrine Reviews, 1997Co-Authors: Roy G Smith, Ravi P Nargund, Kang Cheng, Scott D Feighner, Andrew D. Howard, Lex H T Van Der Ploeg, Gerard J Hickey, Matthew J Wyvratt, Michael H Fisher, Arthur A. PatchettAbstract:I. Introduction II. Identification of Peptidomimetic GH Secretagogues A. Mechanism of action of GHRH, GHRP-6, and somatostatin B. In vitro assays III. Molecular Design by Medicinal Chemistry A. Benzolactams and L-692,429 B. Spiroindanes and MK-0677 C. Isonipecotic acid peptidomimetics IV. Characterization of the MK-0677 Receptor A. Pituitary gland B. Hypothalamus V. Signal Transduction Pathway VI. Cloning the GH Secretagogue Receptor A. Chromosomal localization VII. Action of the Peptidomimetic GH Secretagogues in the Central Nervous System VIII. Peptidomimetic GH Secretagogues in Vivo A. Animal models B. Clinical studies in humans IX. Regulation of Pulsatile GH Release A. GHRH and somatostatin B. The role of GHS-R X. Concluding Comments
Arthur A. Patchett - One of the best experts on this subject based on the ideXlab platform.
-
potent 3 spiropiperidine growth hormone Secretagogues
ChemInform, 2010Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Kang Cheng, Roy G Smith, Klaus D. Schleim, Tom Jacks, Wanda Chan, Arthur A. PatchettAbstract:Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone Secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford Secretagogues with low nanomolar in vitro activity.
-
synthesis and biological activities of spiroheterocyclic growth hormone Secretagogues
ChemInform, 1999Co-Authors: Menghsin Chen, Wanda W.-s. Chan, Arthur A. Patchett, Kang Cheng, Liente Wei, Bridget Butler, Tom Jacks, Patrick P Pollard, Roy G SmithAbstract:The synthesis and biological activities of a series of spiroheterocyclic growth hormone Secretagogues are reported. Modification of the spiroindane part-structure of the prototypal Secretagogue L-162,752 revealed that the spiroindane could be replaced with spirobenzodihydrothiophen derivatives to enhance not only in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4-cyclohexylbutanoic analogs (8a-8d) were also identified to be active Secretagogues.
-
Tripeptide growth hormone Secretagogues
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Wanda W.-s. Chan, Ravi P Nargund, Kang Cheng, Roy G Smith, Khaled Barakat, Arthur A. PatchettAbstract:Abstract A series of C-terminus capped dipeptides and tripeptides was synthesized as growth hormone (GH) Secretagogues. Among them, tripeptide Aib-D-Trp-D-homoPhe-OEt showed low nanomolar activity in the rat pituitary assay. Thus, we have demonstrated that the GH Secretagogue activity of the hexa- hepta-GH releasing peptides can be mimicked at the tripeptide level.
-
peptidomimetic regulation of growth hormone secretion
Endocrine Reviews, 1997Co-Authors: Roy G Smith, Ravi P Nargund, Kang Cheng, Scott D Feighner, Andrew D. Howard, Lex H T Van Der Ploeg, Gerard J Hickey, Matthew J Wyvratt, Michael H Fisher, Arthur A. PatchettAbstract:I. Introduction II. Identification of Peptidomimetic GH Secretagogues A. Mechanism of action of GHRH, GHRP-6, and somatostatin B. In vitro assays III. Molecular Design by Medicinal Chemistry A. Benzolactams and L-692,429 B. Spiroindanes and MK-0677 C. Isonipecotic acid peptidomimetics IV. Characterization of the MK-0677 Receptor A. Pituitary gland B. Hypothalamus V. Signal Transduction Pathway VI. Cloning the GH Secretagogue Receptor A. Chromosomal localization VII. Action of the Peptidomimetic GH Secretagogues in the Central Nervous System VIII. Peptidomimetic GH Secretagogues in Vivo A. Animal models B. Clinical studies in humans IX. Regulation of Pulsatile GH Release A. GHRH and somatostatin B. The role of GHS-R X. Concluding Comments
-
mk 0677 a potent novel orally active growth hormone gh Secretagogue gh insulin like growth factor i and other hormonal responses in beagles
Endocrinology, 1996Co-Authors: Tom Jacks, Ravi P Nargund, Roy G Smith, Klaus D. Schleim, F Judith, Howard Y Chen, E Frazier, D Krupa, Donald F Hora, Arthur A. PatchettAbstract:MK-0677, a spiroindoline sulfonamide, is a novel, orally active GH Secretagogue. The effects of MK-0677 on serum GH and other hormones after oral and iv single dose administrations in beagles were evaluated. After oral administration in a balanced eight-dog crossover study, treatment with MK-0677 significantly increased peak GH concentrations, with a 5.3-fold increase (mean +/- SEM, 10.5 +/- 1.9 ng/ml) at the 0.25 mg/kg dose, a 9.0-fold increase (18.0 +/- 3.3 ng/ml) at the 0.50 mg/kg dose, and a 15.8-fold increase (31.6 +/- 5.8 ng/ml) at the 1.0 mg/kg dose. Total GH release, expressed as the area under the curve, showed similar significant increases over the effect of the water placebo. A single oral 1 mg/kg dose in three dogs induced a mean GH peak of 27.6 +/- 1.5 ng/ml at 120 min, and GH levels remained elevated up to 360 min after treatment. Insulin-like growth factor I (IGF-I) levels were significantly increased by 30% at 480 min after treatment. Cortisol levels were increased 2.4-fold over pretreatment levels. After i.v. administration, compared to the saline control group which had a mean (+/- SEM) serum GH peak of 3.8 +/- 0.7 ng/ml, MK-0677 at 0.25 mg/kg significantly increased (P < 0.05) peak GH concentrations 20.4-fold (77.4 +/- 13.7 ng/ml). Total GH release, expressed as the area under the curve, showed a similar increase. The mean peak GH level was recorded 10 min after treatment, with GH levels elevated up to 180 min after treatment. IGF-I levels were significantly elevated by 25% 360 min after the administration of MK-0677. Cortisol levels were increased 2.3-fold over pretreatment levels. Insulin and glucose levels were higher, LH and PRL levels were unaltered, and T4 levels were marginally lower; the levels of each of these hormones remained within the normal ranges for dogs throughout the experiment. In summary, MK-0677 is a potent GH Secretagogue that induces an immediate, large, long lasting increase in GH levels when administered orally or i.v. In contrast to GH-releasing peptide-6 and benzolactam Secretagogues, GH levels were elevated up to 360 min after treatment, and this was associated with a significant increase in IGF-I levels. Cortisol levels were increased; however, the increases were modest compared to those in GH.
Suzanne L Dickson - One of the best experts on this subject based on the ideXlab platform.
-
the rat arcuate nucleus integrates peripheral signals provided by leptin insulin and a ghrelin mimetic
Diabetes, 2002Co-Authors: A K Hewson, Loraine Y C Tung, David W Connell, Laura Tookman, Suzanne L DicksonAbstract:The hypothalamic circuits controlling food intake and body weight receive and integrate information from circulating satiety signals such as leptin and insulin and also from ghrelin, the only known circulating hormone that stimulates appetite following systemic injection. Activation of arcuate neurons by ghrelin and ghrelin mimetics (the growth hormone Secretagogues) is augmented in 48-h-fasted rats compared with fed rats, as reflected by a greater number of cells expressing Fos protein in response to administration of the same maximally effective dose. Here we sought to determine whether this increased responsiveness in fasting might reflect or be influenced by low levels of circulating satiety factors such as leptin or insulin. Chronic central infusion of insulin or leptin during a 48-h fast suppressed the threefold increase in the Fos response to intravenous injection of a maximally effective dose of growth hormone-releasing peptide (GHRP)-6, a synthetic growth hormone Secretagogue. This appears to be a direct central action of insulin and leptin because the marked decrease in plasma levels of insulin, leptin, and glucose during fasting were unaffected by central administration of either hormone. Furthermore, the GHRP-6-induced Fos response was twofold greater in obese leptin- and insulin-resistant Zucker rats compared with lean controls. These data provide evidence that the ghrelin-sensitive circuits in the hypothalamus are dynamically regulated by central insulin and leptin action.
-
chronic central infusion of growth hormone Secretagogues effects on fos expression and peptide gene expression in the rat arcuate nucleus
Neuroendocrinology, 1999Co-Authors: Alex R T Bailey, Roy G Smith, Gareth Leng, Michelle E Giles, Colin H Brown, Philip M Bull, Lynn P Macdonald, Lynsey C Smith, Suzanne L DicksonAbstract:Growth hormone (GH) Secretagogues induce GH release, in part, by direct actions upon anterior pituitary somatotropes and, in part, by actions upon the neuroendocrine circuitry that regulates GH secretion. In particular, acute systemic administration of GH Secretagogues results in increased neuronal activity and Fos protein expression in the arcuate nucleus of the hypothalamus. Prolonged administration of GH Secretagogues has been reported to have long-lasting effects upon GH release, promoting increased pulsatile secretion. Here, we investigated how chronic central infusion of GH Secretagogues affects the response of arcuate nucleus neurons to acute systemic administration of GH Secretagogues. In male rats, after central infusion of GH Secretagogues for 5 days, there was no sustained expression of Fos in the arcuate nucleus, no significant induction of Fos expression in response to acute GH Secretagogue challenge, and a greatly attenuated secretion of GH in response to acute GH Secretagogue challenge, all reflecting loss of funtional responsiveness to GH Secretagogues. In situ hybridisation revealed that, in the arcuate nucleus of GH Secretagogue-infused rats, mRNA levels for GH-releasing hormone, neuropeptide Y and somatostatin were not different than in saline-infused animals. However, somatostatin mRNA levels in the periventricular nuclei of GH Secretagogue-infused rats were significantly higher than those of saline-infused rats, indicating that this nucleus may play an important role in mediating the effects of chronic GH Secretagogue administration.
Ravi P Nargund - One of the best experts on this subject based on the ideXlab platform.
-
Tripeptide growth hormone Secretagogues
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Wanda W.-s. Chan, Ravi P Nargund, Kang Cheng, Roy G Smith, Khaled Barakat, Arthur A. PatchettAbstract:Abstract A series of C-terminus capped dipeptides and tripeptides was synthesized as growth hormone (GH) Secretagogues. Among them, tripeptide Aib-D-Trp-D-homoPhe-OEt showed low nanomolar activity in the rat pituitary assay. Thus, we have demonstrated that the GH Secretagogue activity of the hexa- hepta-GH releasing peptides can be mimicked at the tripeptide level.
-
peptidomimetic regulation of growth hormone secretion
Endocrine Reviews, 1997Co-Authors: Roy G Smith, Ravi P Nargund, Kang Cheng, Scott D Feighner, Andrew D. Howard, Lex H T Van Der Ploeg, Gerard J Hickey, Matthew J Wyvratt, Michael H Fisher, Arthur A. PatchettAbstract:I. Introduction II. Identification of Peptidomimetic GH Secretagogues A. Mechanism of action of GHRH, GHRP-6, and somatostatin B. In vitro assays III. Molecular Design by Medicinal Chemistry A. Benzolactams and L-692,429 B. Spiroindanes and MK-0677 C. Isonipecotic acid peptidomimetics IV. Characterization of the MK-0677 Receptor A. Pituitary gland B. Hypothalamus V. Signal Transduction Pathway VI. Cloning the GH Secretagogue Receptor A. Chromosomal localization VII. Action of the Peptidomimetic GH Secretagogues in the Central Nervous System VIII. Peptidomimetic GH Secretagogues in Vivo A. Animal models B. Clinical studies in humans IX. Regulation of Pulsatile GH Release A. GHRH and somatostatin B. The role of GHS-R X. Concluding Comments
-
structural requirements for the activation of the human growth hormone Secretagogue receptor by peptide and nonpeptide Secretagogues
Molecular Endocrinology, 1997Co-Authors: Scott D Feighner, Kristine Prendergast, Ravi P Nargund, Oksana C Palyha, Andrew D. Howard, Donna L Hreniuk, Dennis J Underwood, James R Tata, Dennis C Dean, Carina P TanAbstract:Antibodies raised against an intracellular and extracellular domain of the GH Secretagogue receptor (GHS-R) confirmed that its topological orientation in the lipid bilayer is as predicted for G protein-coupled receptors with seven transmembrane domains. A strategy for mapping the agonist-binding site of the human GHS-R was conceived based on our understanding of ligand binding in biogenic amine and peptide hormone G protein-coupled receptors. Using site-directed mutagenesis and molecular modeling, we classified GHS peptide and nonpeptide agonist binding in the context of its receptor environment. All peptide and nonpeptide ligand classes shared a common binding domain in transmembrane (TM) region 3 of the GHS-R. This finding was based on TM-3 mutation E124Q, which eliminated the counter-ion to the shared basic N+ group of all GHSs and resulted in a nonfunctional receptor. Restoration of function for the E124Q mutant was achieved by a complementary change in the MK-0677 ligand through modification of its a...
-
mk 0677 a potent novel orally active growth hormone gh Secretagogue gh insulin like growth factor i and other hormonal responses in beagles
Endocrinology, 1996Co-Authors: Tom Jacks, Ravi P Nargund, Roy G Smith, Klaus D. Schleim, F Judith, Howard Y Chen, E Frazier, D Krupa, Donald F Hora, Arthur A. PatchettAbstract:MK-0677, a spiroindoline sulfonamide, is a novel, orally active GH Secretagogue. The effects of MK-0677 on serum GH and other hormones after oral and iv single dose administrations in beagles were evaluated. After oral administration in a balanced eight-dog crossover study, treatment with MK-0677 significantly increased peak GH concentrations, with a 5.3-fold increase (mean +/- SEM, 10.5 +/- 1.9 ng/ml) at the 0.25 mg/kg dose, a 9.0-fold increase (18.0 +/- 3.3 ng/ml) at the 0.50 mg/kg dose, and a 15.8-fold increase (31.6 +/- 5.8 ng/ml) at the 1.0 mg/kg dose. Total GH release, expressed as the area under the curve, showed similar significant increases over the effect of the water placebo. A single oral 1 mg/kg dose in three dogs induced a mean GH peak of 27.6 +/- 1.5 ng/ml at 120 min, and GH levels remained elevated up to 360 min after treatment. Insulin-like growth factor I (IGF-I) levels were significantly increased by 30% at 480 min after treatment. Cortisol levels were increased 2.4-fold over pretreatment levels. After i.v. administration, compared to the saline control group which had a mean (+/- SEM) serum GH peak of 3.8 +/- 0.7 ng/ml, MK-0677 at 0.25 mg/kg significantly increased (P < 0.05) peak GH concentrations 20.4-fold (77.4 +/- 13.7 ng/ml). Total GH release, expressed as the area under the curve, showed a similar increase. The mean peak GH level was recorded 10 min after treatment, with GH levels elevated up to 180 min after treatment. IGF-I levels were significantly elevated by 25% 360 min after the administration of MK-0677. Cortisol levels were increased 2.3-fold over pretreatment levels. Insulin and glucose levels were higher, LH and PRL levels were unaltered, and T4 levels were marginally lower; the levels of each of these hormones remained within the normal ranges for dogs throughout the experiment. In summary, MK-0677 is a potent GH Secretagogue that induces an immediate, large, long lasting increase in GH levels when administered orally or i.v. In contrast to GH-releasing peptide-6 and benzolactam Secretagogues, GH levels were elevated up to 360 min after treatment, and this was associated with a significant increase in IGF-I levels. Cortisol levels were increased; however, the increases were modest compared to those in GH.
-
design and biological activities of l 163 191 mk 0677 a potent orally active growth hormone Secretagogue
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Arthur A. Patchett, Wanda W.-s. Chan, Ravi P Nargund, Kang Cheng, B Butler, J R Tata, M H Chen, K J Barakat, D B Johnston, G J HickeyAbstract:A potent, orally active growth hormone (GH) Secretagogue L-163,191 belonging to a recently synthesized structural class has been characterized. L-163,191 releases GH from rat pituitary cells in culture with EC50 = 1.3 +/- 0.09 nM and is mechanistically indistinguishable from the GH-releasing peptide GHRP-6 and the prototypical nonpeptide GH Secretagogue L-692,429 but clearly distinguishable from the natural GH Secretagogue, GH-releasing hormone. L-163,191 elevates GH in dogs after oral doses as low as 0.125 mg/kg and was shown to be specific in its release of GH without significant effect on plasma levels of aldosterone, luteinizing hormone, thyroxine, and prolactin after oral administration of 1 mg/kg. Only modest increases in cortisol were observed. Based on these properties, L-163,191 has been selected for clinical studies.
Kang Cheng - One of the best experts on this subject based on the ideXlab platform.
-
potent 3 spiropiperidine growth hormone Secretagogues
ChemInform, 2010Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Kang Cheng, Roy G Smith, Klaus D. Schleim, Tom Jacks, Wanda Chan, Arthur A. PatchettAbstract:Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone Secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford Secretagogues with low nanomolar in vitro activity.
-
synthesis and biological activities of spiroheterocyclic growth hormone Secretagogues
ChemInform, 1999Co-Authors: Menghsin Chen, Wanda W.-s. Chan, Arthur A. Patchett, Kang Cheng, Liente Wei, Bridget Butler, Tom Jacks, Patrick P Pollard, Roy G SmithAbstract:The synthesis and biological activities of a series of spiroheterocyclic growth hormone Secretagogues are reported. Modification of the spiroindane part-structure of the prototypal Secretagogue L-162,752 revealed that the spiroindane could be replaced with spirobenzodihydrothiophen derivatives to enhance not only in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4-cyclohexylbutanoic analogs (8a-8d) were also identified to be active Secretagogues.
-
Tripeptide growth hormone Secretagogues
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Lihu Yang, Greg Morriello, Kristine Prendergast, Wanda W.-s. Chan, Ravi P Nargund, Kang Cheng, Roy G Smith, Khaled Barakat, Arthur A. PatchettAbstract:Abstract A series of C-terminus capped dipeptides and tripeptides was synthesized as growth hormone (GH) Secretagogues. Among them, tripeptide Aib-D-Trp-D-homoPhe-OEt showed low nanomolar activity in the rat pituitary assay. Thus, we have demonstrated that the GH Secretagogue activity of the hexa- hepta-GH releasing peptides can be mimicked at the tripeptide level.
-
peptidomimetic regulation of growth hormone secretion
Endocrine Reviews, 1997Co-Authors: Roy G Smith, Ravi P Nargund, Kang Cheng, Scott D Feighner, Andrew D. Howard, Lex H T Van Der Ploeg, Gerard J Hickey, Matthew J Wyvratt, Michael H Fisher, Arthur A. PatchettAbstract:I. Introduction II. Identification of Peptidomimetic GH Secretagogues A. Mechanism of action of GHRH, GHRP-6, and somatostatin B. In vitro assays III. Molecular Design by Medicinal Chemistry A. Benzolactams and L-692,429 B. Spiroindanes and MK-0677 C. Isonipecotic acid peptidomimetics IV. Characterization of the MK-0677 Receptor A. Pituitary gland B. Hypothalamus V. Signal Transduction Pathway VI. Cloning the GH Secretagogue Receptor A. Chromosomal localization VII. Action of the Peptidomimetic GH Secretagogues in the Central Nervous System VIII. Peptidomimetic GH Secretagogues in Vivo A. Animal models B. Clinical studies in humans IX. Regulation of Pulsatile GH Release A. GHRH and somatostatin B. The role of GHS-R X. Concluding Comments
-
design and biological activities of l 163 191 mk 0677 a potent orally active growth hormone Secretagogue
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Arthur A. Patchett, Wanda W.-s. Chan, Ravi P Nargund, Kang Cheng, B Butler, J R Tata, M H Chen, K J Barakat, D B Johnston, G J HickeyAbstract:A potent, orally active growth hormone (GH) Secretagogue L-163,191 belonging to a recently synthesized structural class has been characterized. L-163,191 releases GH from rat pituitary cells in culture with EC50 = 1.3 +/- 0.09 nM and is mechanistically indistinguishable from the GH-releasing peptide GHRP-6 and the prototypical nonpeptide GH Secretagogue L-692,429 but clearly distinguishable from the natural GH Secretagogue, GH-releasing hormone. L-163,191 elevates GH in dogs after oral doses as low as 0.125 mg/kg and was shown to be specific in its release of GH without significant effect on plasma levels of aldosterone, luteinizing hormone, thyroxine, and prolactin after oral administration of 1 mg/kg. Only modest increases in cortisol were observed. Based on these properties, L-163,191 has been selected for clinical studies.
