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

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

19 Citaten (Scopus)

Samenvatting

Cushing's disease, a hypercortisolemic state induced by an ACTH overexpressing pituitary adenoma, causes increased morbidity and mortality. Selective antagonism of the melanocortin type 2 receptor (MC2R) may be a novel treatment modality. Five structurally related peptides with modified HFRW sites but intact putative MC2R binding sites were tested for antagonistic activity at MC1R, MC2R/MRAP, MC3R, MC4R and MC5R. Two of these peptides (GPS1573 and GPS1574) dose-dependently antagonized ACTH-stimulated MC2R activity (IC50s of 66±23nM and 260±1nM, respectively). GPS1573 and 1574 suppressed the Rmax but not EC50 of ACTH on MC2R, indicating non-competitive antagonism. These peptides did not antagonize α-MSH stimulation of MC1R and antagonized MC3, 4 and 5R at markedly lower potency. GP1573 and GPS1574 antagonize MC4R with IC50s of 950nM and 3.7μM, respectively. In conclusion, two peptide antagonists were developed with selectivity for MC2R, forming a platform for development of a medical treatment for Cushing's disease.

Originele taal-2Engels
Pagina's (van-tot)99-104
Aantal pagina's6
TijdschriftMolecular and Cellular Endocrinology
Volume394
Nummer van het tijdschrift1-2
DOI's
StatusGepubliceerd - 25 aug. 2014
Extern gepubliceerdJa

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