A Nonpeptidyl Growth Hormone Secretagogue

Smith, Roy G.; Cheng, Kang; Schoen, William R.; Pong, Sheng-Shung; Hickey, Gerard J.; Jacks, T. J.; Butler, Bridget; Chan, Wanda; Chaung, L Y; Judith, F. R.

doi:10.1126/science.8503009

Cited by 331 publications

(150 citation statements)

References 18 publications

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“…GHS induces calcium flux in rat pituitary cells, and causes the release of GH (10). The release of GH is similar to physiological release of GH in that it is under pulsating regimen and is subjected to feedback mechanism (11).…”

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confidence: 84%

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Immune Enhancing Effect of a Growth Hormone Secretagogue

Koo¹,

Huang²,

Camacho³

et al. 2001

The Journal of Immunology

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104

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Growth hormone (GH) has been known to enhance immune responses, whether directly or through the insulin like growth factor-1, induced by GH. Recently a nonpeptidyl small m.w. compound, a GH secretagogue (GHS), was found to induce the production of GH by the pituitary gland. In this study, we examined the effect of GHS in immunological functions of 5- to 6-wk-old and 16- to 24-month-old mice. In young mice, we observed a significant increase in PBLs, but T and B cell-proliferative responses were not consistently enhanced. The old mice, treated with GHS for 3 wk, did not show increases in peripheral lymphocytes, but they exhibited a statistically significant increase in thymic cellularity and differentiation. When inoculated with a transplantable lymphoma cell line, EL4, the treated old mice showed statistically significant resistance to the initiation of tumors and the subsequent metastases. Generation of CTL to EL4 cells was also enhanced in the treated mice, suggesting that GHS has a considerable immune enhancing effect, particularly in the old mice. We have also found that GHS promoted better thymic engraftment in bone marrow transplant of SCID mice. We found more cycling cells in the spleens of treated mice, suggesting that GHS may exert its immune enhancing effect by promoting cell division in lymphoid cells. These observations ascribe to GHS a novel therapy possible for aging, AIDS, and transplant individuals, whose immune functions are compromised.

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confidence: 84%

“…The GHS compound was previously published (10) and prepared at Merck. It is an analog of MK677, which was in clinical trials (11,16).…”

Section: Compound Dosagementioning

confidence: 99%

Immune Enhancing Effect of a Growth Hormone Secretagogue

Koo¹,

Huang²,

Camacho³

et al. 2001

The Journal of Immunology

Self Cite

104

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“…In recent years, smallmolecule agonists have been described, even for receptors for larger hormones like insulin, TPO, and EPO (18)(19)(20), but none of these receptors belong to the GPCR superfamily. Within the GPCRs, small-molecule agonists have been described, e.g., for the arginine vasopressin V-2 receptor, the somatostatin receptor, the bradykinin receptor, the cholecystokinin receptor, the angiotensin II receptor, and the growth hormone secretagogue receptor (21)(22)(23)(24)(25)(26). However, none of these GPCRs belong to the B family, and the natural ligands are all either fairly small or have a defined secondary structure.…”

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confidence: 99%

“…Exenatide, a GLP-1 analog originally isolated from the saliva of the Gila monster, recently was approved by the Food and Drug Administration as a twice-daily treatment regimen (13). Liraglutide [N-(␥-L-glutamoyl(N-␣-hexadecanoyl)-Lys 26 ,Arg 34 -GLP-1(7-37)] is a long-acting analog in phase 3 clinical development as a once-daily treatment regimen (14,15). However, as peptides, GLP-1 and analogs thereof have to be administered by injection.…”

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confidence: 99%

Small-molecule agonists for the glucagon-like peptide 1 receptor

Knudsen¹,

Kiel

Teng

et al. 2007

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

193

205

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The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.ago-allosteric modulator ͉ allosteric ͉ G protein-coupled receptor ͉ screening ͉ cAMP

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“…For example, a minor change in GHRP-6 (a GH-releasing peptide) by replacing D-lysine with alanine can change the GHS specificity of GHRP-6, and create a new biomolecule with antagonist effects on GHS-R (3). A synthetic peptidic, ghrelin antagonist [D-Lys3] GHRP-6 (HisDTrp-DLys-Trp-DPhe-Lys-NH2) (Figure 1) is widely utilized in vivo and in vitro as the preferred ghrelin receptor (3,4). Ghrelin was identified as the strongest GH-stimulator peptide (5).…”

Section: Introductionmentioning

confidence: 99%

Effects of peptidic growth hormone secretagogue receptor (GHS-R) antagonist [D-Lys3] on some of serum hormonal and biochemical parameters in Wistar rat model

Shahryar

Lotfi

2014

Arq Bras Endocrinol Metab

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Objective: The present study investigated the effects of different dosages of a GHS-R antagonist on some serum hormonal (cortisol, T 3 and T 4 ) and biochemical parameters in a rat. Materials and methods: Thirty-six 60-day-old male rats were assigned to four treatments. [D--Lys3]-GHRP-6 solutions were infused via intraperitoneal injections. Blood was collected and analyzed. Results: The large dosages of a GHS-R antagonist (200 ng/kg BW) caused increases in cortisol, whereas no significant changes occurred when low dosages were injected. There were no significant changes in T 3 and T 4 following the administration of the GHS-R antagonist, but a considerable increase was observed in blood glucose levels of the groups (G50, G100, and G200 ng/kg BW). There was a significant increase in total protein when the greatest dose was administrated (G200 ng/kg BW). However, total cholesterol, triglycerides, and albumin showed no significant changes. Conclusions: Exogenous GHS-R antagonist can cause an increase in glucose and moderate increases in cortisol and total protein, yet it has no significant effect on T 3 and T 4 levels or on the concentrations of serum lipids. The effect of GHS-R antagonist is not completely adverse to the effects of ghrelin. Further molecular studies are necessary to identify the physiological effects of the peptidic GHS-R antagonist. Arq Bras Endocrinol Metab. 2014;58(3):288-91 Keywords Ghrelin receptor; GHS-R; GH-releasing; regulatory peptide; peripheral infusion RESUMO Objetivo: O presente estudo investigou os efeitos de diferentes doses do antagonista do GHS-R [D-Lys3] sobre alguns parâmetros hormonais (cortisol, T 3 e T 4 ) e bioquímicos em ratos. Materiais e métodos: Trinta e seis ratos machos com 60 dias de idade foram alocados para quatro tratamentos. Soluções de [D-Lys3]-GHRP-6 foram administradas por meio de injeções intraperitoneais e foram coletadas e analisadas amostras. Resultados: Doses altas de antagonista de GHS--R (200 ng/kg PC) levaram a aumento do cortisol, enquanto não houve diferença significativa quando foram injetadas doses baixas. Não houve alterações significativas em T 3 e T 4 depois da administração do antagonista do GHS-R, mas foi observado aumento considerável nos níveis de glicose sanguínea dos grupos (G50, G100 e G200 ng/kg PC). Houve aumento significativo na proteína total quando foi administrada a maior dose (G200 ng/kg PC), entretanto, não foram observadas alterações no colesterol total, nos triglicérides e na albumina. Conclusões: O antagonista do GHS-R exógeno pode causar aumento da glicose e aumento moderado do cortisol e proteína total, embora não haja efeitos significativos nos níveis de T 3 e T 4 ou na concentração de lipídios séricos. O efeito do antagonista de GHS-R não é completamente adverso aos efeitos da grelina. Devem ser feitos outros estudos moleculares para se identificar os efeitos fisiológicos do peptídeo antagonista do GHS-R. Arq Bras Endocrinol Metab. 2014;58(3):288-91 DescritoresReceptor da grelina, GHS-R, liberação de GH, peptídeo re...

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A Nonpeptidyl Growth Hormone Secretagogue

Cited by 331 publications

References 18 publications

Immune Enhancing Effect of a Growth Hormone Secretagogue

Immune Enhancing Effect of a Growth Hormone Secretagogue

Small-molecule agonists for the glucagon-like peptide 1 receptor

Effects of peptidic growth hormone secretagogue receptor (GHS-R) antagonist [D-Lys3] on some of serum hormonal and biochemical parameters in Wistar rat model

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