Development of potent selective competitive-antagonists of the melanocortin type 2 receptor

Bouw, Elise; Huisman, Martin; Neggers, Sebastian J C M M; Themmen, Axel P. N.; Lely, Aart-Jan van der; Delhanty, Patric J. D.

doi:10.1016/j.mce.2014.07.003

Cited by 20 publications

(18 citation statements)

References 39 publications

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“…The cells from adult adrenal glands showed significant inhibition of the corticosterone response to ACTH in vitro , with GPS1573 being more potent than GPS1574. A similar response was observed in PD2 pup adrenal cells, as previously described for adult rats ( 17 ). In PD8 pup adrenal cells, however, there was equivalent inhibition between GPS1573 and GPS1574, compared to vehicle control.…”

Section: Resultssupporting

confidence: 86%

“…Dams were allowed to deliver and care for their pups without interference until experimentation. The MC2R antagonists GPS1573 and GPS1574 were synthesized by Genepep (St. Jean de Védas, France) and reconstituted, as described previously ( 17 ).…”

Section: Methodsmentioning

confidence: 99%

“…In the GPS1574 studies, pups (both sexes, N = 42) were only studied at PD2, with the 60-min time point omitted because of drug’s limited supply, the data from the 60-min time point with GPS1573 described above, higher necessary dose based on the in vitro studies [current experiments and Ref. ( 17 )], and its expense. GPS1574 was given at a dose of 4 or 8 mg/kg ip.…”

Section: Methodsmentioning

confidence: 99%

“…GPS1573 (Nle-P-f-R-w-F-K-A-V-G-K-K-R-R NH 2 ) and GPS1574 [Nle-(E-f-R-w-F-K)-A-V-G-K-K-R-R NH 2 ] are newly described, potent (IC 50 = 66 ± 23 and 260 ± 1 nM, respectively), and dose-dependent antagonists of ACTH-stimulated MC2R activity in vitro ( 17 ). Note that the structures of the two compounds are similar except that GPS1574 has a ring structure.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Novel Melanocortin Type 2 Receptor Antagonists on the Corticosterone Response to ACTH in the Neonatal Rat Adrenal Gland In Vivo and In Vitro

et al. 2016

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Stress-induced increases in neonatal corticosterone demonstrate a unique shift from ACTH independence to ACTH dependence between postnatal day 2 (PD2) and day 8 (PD8) in newborn rats. This shift could be due to the binding of a bioactive, non-immunoreactive plasma ligand to the adrenocortical melanocortin 2 receptor (MC2R) (ACTH receptor). A potent MC2R antagonist would be useful to evaluate this phenomenon in the neonate. Therefore, we investigated the acute corticosterone response to ACTH(1–39) injection in rat pups pretreated with newly developed MC2R antagonists (GPS1573 and GPS1574), which have not been tested in vivo. The doses used in vivo were based on their in vitro potency, with GP1573 being more potent than GPS1574. GPS1573 (PD2 and PD8), GPS1574 (PD2 only), or vehicle were injected intraperitoneally (ip) 10 min before baseline sampling. Then, 0.001 mg/kg of ACTH(1–39) was injected ip, and subsequent blood samples obtained for the measurement of plasma corticosterone. Pretreatment of PD2 pups with GPS1573 demonstrated augmentation, rather than inhibition, of the corticosterone response to ACTH. In PD8 pups, pretreatment with 0.1 mg/kg GPS1573, but not 4 mg/kg, augmented the corticosterone response to ACTH. Pretreatment with GPS1574 attenuated the plasma corticosterone response to ACTH at 30 min in PD2 pups. The activity of these two compounds in vivo do not match their potency in vitro, with GPS1573 leading to a small augmentation of the corticosterone response to ACTH in vivo while GPS1574 resulted in inhibition.

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Novel Melanocortin Type 2 Receptor Antagonists on the Corticosterone Response to ACTH in the Neonatal Rat Adrenal Gland In Vivo and In Vitro

et al. 2016

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“…The discovery of MRAP and MRAP2 has initiated a paradigm shift in our understanding of MCR and GPCR signaling (Figure 1 ). For MRAP, the ability to functionally express MC2R in non-adrenal cell lines has opened up many opportunities including screening for MC2R peptide antagonists (Bouw et al, 2014 ). Moreover, the finding that MRAP2 is associated with mammalian obesity is exciting and could provide a novel therapeutic target at a time when obesity is at epidemic levels.…”

Section: Future Of Mrapsmentioning

confidence: 99%

Melanocortin receptor accessory proteins in adrenal disease and obesity

et al. 2015

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Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms.

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Melanocortin 2 receptor antagonists in canine pituitary-dependent hypercortisolism: in vitro studies

et al. 2018

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Canine hypercortisolism is most often caused by an ACTH-secreting pituitary adenoma (pituitary-dependent hypercortisolism; PDH). An interesting target for a selective medical treatment of PDH would be the receptor for ACTH: the melanocortin 2 receptor (MC2R). In this study we investigated whether two peptide compounds, BIM-22776 (#776) and BIM-22A299 (#299), are effective MC2R antagonists in vitro. Their effects on cortisol production and mRNA expression of steroidogenic enzymes, MC2R and melanocortin 2 receptor accessory protein (MRAP) were evaluated in primary adrenocortical cell cultures (n = 8) of normal canine adrenal glands. Cortisol production stimulated by 50 nM ACTH was dose-dependently inhibited by #299 (inhibition 90.7 ± 2.3% at 5 μM) and by #776 (inhibition 38.0 ± 5.2% at 5 μM). The ACTH-stimulated mRNA expression of steroidogenic enzymes, MC2R and MRAP was significantly inhibited by both compounds, but most potently by #299. These results indicate that canine primary cell culture is a valuable in vitro system to test MC2R antagonists, and that these compounds, but especially #299, are effective MC2R antagonists in vitro. To determine its efficacy in vivo, further studies are warranted. Antagonism of the MC2R is a promising potential treatment approach in canine PDH.

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Development of potent selective competitive-antagonists of the melanocortin type 2 receptor

Cited by 20 publications

References 39 publications

Effect of Novel Melanocortin Type 2 Receptor Antagonists on the Corticosterone Response to ACTH in the Neonatal Rat Adrenal Gland In Vivo and In Vitro

Effect of Novel Melanocortin Type 2 Receptor Antagonists on the Corticosterone Response to ACTH in the Neonatal Rat Adrenal Gland In Vivo and In Vitro

Melanocortin receptor accessory proteins in adrenal disease and obesity

Melanocortin 2 receptor antagonists in canine pituitary-dependent hypercortisolism: in vitro studies

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