Pharmacological characterisation of a new oral GH secretagogue, NN703

Hansen, BS; Raun, Kirsten; Nielsen, KK; Pb, Johansen; Hansen, T. K.; Peschke, Bernd; Lau, Jesper; Andersen, PH; Ankersen, Michael

doi:10.1530/eje.0.1410180

Cited by 59 publications

(41 citation statements)

References 39 publications

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“…5D), which could be used for in vivo studies to further establish the mechanism of anticonvulsant action of ghrelin [233]. In turn, non-peptide agonists have also been developed [234,235], including NN703 (Fig. 5E), MK-677 (Fig.…”

Section: Ghrelinmentioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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Section: Ghrelinmentioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…When a stable response was obtained at all frequencies, the frequency spectrum was repeated in the presence of either motilin (10 Ϫ9 M), ghrelin (1-23) oct (10 Ϫ5 M), or GHRP-6 (10 Ϫ5 M) after a preincubation period of 15 min. To evaluate the effect of antagonists, the frequency spectrum was first repeated in the presence of the motilin antagonist GM-109 (10 Ϫ6 M; Takanashi et al, 1995), the GHRP-6 antagonist D-Lys 3 -GHRP-6 (10 Ϫ5 M; Hansen et al, 1999), the NK 1 antagonist (SR140333) (5 ϫ 10 Ϫ7 M; Holzer et al, 1998), the NK 2 antagonist (SR48968) (5 ϫ 10 jpet.aspetjournals.org of antagonists ϩ motilin or GHRP-6 in the same strip preparation. The response was calculated as the mean response during (on-response) and after (off-response) the stimulation period (from integrating the area under the curve) and was expressed in grams per square millimeter.…”

Section: Motilin Receptor Binding Studiesmentioning

confidence: 99%

Interaction of the Growth Hormone-Releasing Peptides Ghrelin and Growth Hormone-Releasing Peptide-6 with the Motilin Receptor in the Rabbit Gastric Antrum

Depoortere

Thijs²,

Thielemans³

et al. 2003

J Pharmacol Exp Ther

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The structural relationship between the motilin and the growth hormone secretagogue receptor (GHS-R), and between their respective ligands, motilin and ghrelin, prompted us to investigate whether ghrelin and the GHS-R agonist growth hormonereleasing peptide-6 (GHRP-6), could interact with the motilin receptor. The interaction was evaluated in the rabbit gastric antrum with binding studies on membrane preparations and with contraction studies on muscle strips in the presence of selective antagonists under conditions of electrical field stimulation (EFS) or not. Binding studies indicated that the affinity (pK d ) for the motilin receptor was in the order of ghrelin (4.23 Ϯ 0.07) Ͻ GHRP-6 (5.54 Ϯ 0.08) Ͻ motilin (9.13 Ϯ 0.03). The interaction of ghrelin with the motilin receptor requires the octanoyl group. Motilin induced smooth muscle contractile responses but ghrelin and GHRP-6 were ineffective. EFS elicited on-and off-responses that were increased by motilin already at 10 Ϫ9 M, but not by 10 Ϫ5 M ghrelin. In contrast, GHRP-6 also enhanced the on-and off-responses. The motilin antagonist Phe-cyclo[Lys-Tyr(3-tBu)-␤Ala-] trifluoroacetate (GM-109) blocked the effect of GHRP-6 on the off-responses but not on the on-responses. Under nonadrenergic noncholinergic conditions, the effects of motilin and GHRP-6 on the on-responses were abolished; those on the off-responses were preserved. All responses were blocked by neurokinin (NK) 1 and NK 2 antagonists. In conclusion, ghrelin is unable to induce contractions via the motilin receptor. However, GHRP-6 enhances neural contractile responses, partially via interaction with the motilin receptor on noncholinergic nerves with tachykinins as mediator, and partially via another receptor that may be a GHS-R subtype on cholinergic nerves that corelease tachykinins.

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“…Leptin-receptor mutated Zucker diabetic fatty (ZDF) and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin (NNC 26-703) (7), and the effects on body weight, food intake and body composition were investigated. Finally, the metabolic effects were correlated to changes induced in the hypothalamic pathways, as reflected by the level of expression of anabolic and catabolic hypothalamic neuropeptides and receptors.…”

Section: Introductionmentioning

confidence: 99%

Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling-deficient ZDF rats

Holm

Ahnfelt-Rønne³

et al. 2004

European Journal of Endocrinology

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Objective: The aim was to investigate the possible interactions of the two peripheral hormones, leptin and ghrelin, that regulate the energy balance in opposite directions. Methods: Leptin-receptor mutated Zucker diabetic fatty (ZDF) and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin (50 mg/kg p.o.) for 18 days, and the effects on body weight, food intake and body composition were investigated. The level of expression of anabolic and catabolic neuropeptides and their receptors in the hypothalamic area were analysed by in situ hybridization. Results: Tabimorelin treatment induced hyperphagia and adiposity (increased total fat mass and gain in body weight) in lean control rats, while these parameters were not increased in ZDF rats. Treatment with tabimorelin of lean control rats increased hypothalamic mRNA expression of the anabolic neuropeptide Y (NPY) mRNA and decreased hypothalamic expression of the catabolic peptide proopiomelanocortin (POMC) mRNA. In ZDF rats, the expression of POMC mRNA was not affected by treatment with tabimorelin, whereas NPY mRNA expression was increased in the hypothalamic arcuate nucleus. Conclusion: This shows that tabimorelin-induced adiposity and hyperphagia in lean control rats are correlated with increased hypothalamic NPY mRNA and decreased POMC mRNA expression. The elimination of tabimorelin-induced adiposity and hyperphagia in ZDF rats may be due to lack of POMC mRNA downregulation. In conclusion, we suggest that ghrelin-receptor ligands exert their adipogenic and orexigenic effects via hypothalamic mechanisms that are dependent on intact leptin-receptor signalling.European Journal of Endocrinology 150 893-904

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Pharmacological characterisation of a new oral GH secretagogue, NN703

Cited by 59 publications

References 39 publications

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Interaction of the Growth Hormone-Releasing Peptides Ghrelin and Growth Hormone-Releasing Peptide-6 with the Motilin Receptor in the Rabbit Gastric Antrum

Adipogenic and orexigenic effects of the ghrelin-receptor ligand tabimorelin are diminished in leptin-signalling-deficient ZDF rats

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