Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats

Johansen, Peter; Nowak, Jette; Skjærbæk, Christian; Flyvbjerg, Allan; Andreassen, Troels T.; Wilken, Michael; Ørskov, Hans

doi:10.1054/ghir.1999.9998

Cited by 21 publications

(21 citation statements)

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“…These experiments demonstrated that GHRP-6, hexarelin and MK677, as expected, were able to inhibit specific 35 S-MK677 binding in a rank order comparable to that found in the rat pituitary cell assay (Table 1 and Fig 2). NN703 also inhibited the binding of the radioactive ligand specifically (Fig.…”

Section: Rat Pituitary Cell Assaysupporting

confidence: 77%

“…2); however, this inhibition occurred with lower potency as compared with GHRP-6, hexarelin and MK677, as would be expected from the rat pituitary cell experiment (Table 2). No binding of 35 S-MK677 was observed to nontransfected BHK and COS-7 cells (data not shown).…”

Section: Rat Pituitary Cell Assaymentioning

confidence: 92%

“…Isolated crude membranes from BHK cells, stably expressing the human GHS-R 1A, were suspended in homogenising buffer (2.5 mmol/l Tris-base, 2.5 mmol/l EDTA, 10 mmol/l MgCl 2 and 30 mg/ml bacitracin) to a concentration of 0.5 mg protein/ml and added to microtitre plates to a final total concentration of 50 mg protein/ml together with 35 S-MK677 (40 000 c.p.m./ well) and with or without different concentrations (0.001 nmol/l to 10 mmol/l) of different GHSs and binding buffer (2.5 mmol/l Tris-base, 2.5 mmol/l EDTA and 10 mmol/l MgCl 2 ) up to a total volume of 250 ml. Non-specific binding was obtained by adding 10 mmol/l MK677.…”

Section: Receptor Binding Assaysmentioning

confidence: 99%

“…For the receptor binding studies, specific binding was defined as the difference between total binding and non-specific binding defined as 35 S-MK677 binding in the absence and presence of 10 mmol/l unlabelled MK677 respectively. Displacement curves were constructed using non-linear regression.…”

Section: Calculationsmentioning

confidence: 99%

“…We further evaluated the specificity of NN703, using binding of 35 S-MK677 to the human GHS-R 1A either stably expressed in a BHK cell line or transiently in COS-7 cells. These experiments demonstrated that GHRP-6, hexarelin and MK677, as expected, were able to inhibit specific 35 S-MK677 binding in a rank order comparable to that found in the rat pituitary cell assay (Table 1 and Fig 2).…”

Section: Rat Pituitary Cell Assaymentioning

confidence: 99%

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Pharmacological characterisation of a new oral GH secretagogue, NN703

Hansen¹,

Raun²,

Nielsen³

et al. 1999

European Journal of Endocrinology

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NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist.Binding of 35S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of 35 S-MK677. However, the observed K i value was lower than expected, as based on the observed potencies regarding GH release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency, when compared with GHRP-6 and MK677, than that observed in rat pituitary cells.The effect of i.v. administration of NN703 on GH and cortisol release was studied in swine. The potency and efficacy of NN703 on GH release were determined to be 155 Ϯ 23 nmol/kg and 91 Ϯ 7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown.The effect of NN703 on GH release after i.v. and oral dosing in beagle dogs was studied. NN703 dosedependently increased the GH release after oral administration. At the highest dose (20 mmol/kg), a 35-fold increase in peak GH concentration was observed (49.5 Ϯ 17.8 ng/ml, mean Ϯ S.E.M.). After a single i.v. dose of 1 mmol/kg the peak GH plasma concentration was elevated to 38.5 Ϯ 19.6 ng/ml (mean Ϯ S.E.M.) approximately 30 min after dosing and returned to basal level after 360 min. The oral bioavailability was 30%. The plasma half-life of NN703 was 4.1 Ϯ 0.4 h.A long-term biological effect of NN703 was demonstrated in a rat study, where the body weight gain was measured during a 14-day once daily oral challenge with 100 mmol/kg. The body weight gain was significantly increased after 14 days as compared with a vehicle-treated group.In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.

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Section: Rat Pituitary Cell Assaysupporting

confidence: 77%

Section: Rat Pituitary Cell Assaymentioning

confidence: 92%

Section: Receptor Binding Assaysmentioning

confidence: 99%

Section: Calculationsmentioning

confidence: 99%

Section: Rat Pituitary Cell Assaymentioning

confidence: 99%

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Pharmacological characterisation of a new oral GH secretagogue, NN703

Hansen¹,

Raun²,

Nielsen³

et al. 1999

European Journal of Endocrinology

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Short Anabolic Peptides for Bone Growth

Amso

Cornish²,

Brimble

2016

Medicinal Research Reviews

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Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth.

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Effects of Jaoga‐Yukmiwon^®, a Korean herbal medicine, on chondrocyte proliferation and longitudinal bone growth in adolescent male rats

Leem

Park

Lee

et al. 2003

Phytotherapy Research

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Externally visible growth of the body is the result of proliferation of chondrocytes and longitudinal bone growth. The effects of the Korean herbal medicine, Jaoga-Yukmiwon((R)), on the growth of adolescent rats were investigated in the present study. The proliferation ratio of chondrocytes was calculated from 5-bromo-2'-deoxyuridine incorporation during DNA synthesis. The 5-bromo-2'-deoxyuridine incorporation ratio of the control group was 21.1 +/- 3.5%, and Jaoga-Yukmiwon((R)) administration markedly increased the ratio to 34.5 +/- 4.6% (p < 0.05). The bone formation rate of longitudinal bone was estimated by labelling with tetracycline, which binds to newly formed bone. The bone formation rate in the tibia of Jaoga-Yukmiwon((R))-administered rats was increased to 405.1 +/- 4.3 micro m (p < 0.05) from 292.2 +/- 11.8 micrometer (control value). The height of the growth plate in the administrated rats was increased to 614.6 +/- 10.0 micro m (p < 0.05) from 552.3 +/- 17.1 micro m. The bone morphogenetic protein-2 immunostaining in the growth plate was also increased. These results suggest that Jaoga-Yukmiwon((R)) may promote longitudinal bone growth during the developmental period.

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Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats

Cited by 21 publications

References 0 publications

Pharmacological characterisation of a new oral GH secretagogue, NN703

Pharmacological characterisation of a new oral GH secretagogue, NN703

Short Anabolic Peptides for Bone Growth

Effects of Jaoga‐Yukmiwon^®, a Korean herbal medicine, on chondrocyte proliferation and longitudinal bone growth in adolescent male rats

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Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats

Cited by 21 publications

References 0 publications

Pharmacological characterisation of a new oral GH secretagogue, NN703

Pharmacological characterisation of a new oral GH secretagogue, NN703

Short Anabolic Peptides for Bone Growth

Effects of Jaoga‐Yukmiwon®, a Korean herbal medicine, on chondrocyte proliferation and longitudinal bone growth in adolescent male rats

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Product

Resources

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Effects of Jaoga‐Yukmiwon^®, a Korean herbal medicine, on chondrocyte proliferation and longitudinal bone growth in adolescent male rats