title: Development of potent selective competitive-antagonists of the melanocortin type 2 receptor.
abstract: 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±23 nM and 260±1 nM, 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 950 nM and 3.7 μM, 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.
authors.affiliation: Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
authors.forename: Elise
authors.initials: E
authors.lastname: Bouw
authors.affiliation: Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Huisman
authors.affiliation: Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
authors.forename: Sebastian J C M M
authors.initials: SJ
authors.lastname: Neggers
authors.affiliation: Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
authors.forename: Axel P N
authors.initials: AP
authors.lastname: Themmen
authors.affiliation: Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Lely
authors.affiliation: Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands. Electronic address: p.delhanty@erasmusmc.nl.
authors.forename: Patric J D
authors.initials: PJ
authors.lastname: Delhanty
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy; D011485:Protein Binding; D044102:Receptor, Melanocortin, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044103:Receptor, Melanocortin, Type 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C505392:MC3R protein, human; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D044103:Receptor, Melanocortin, Type 2; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D000324:Adrenocorticotropic Hormone
keywords: Adrenocorticotropic hormone (ACTH); Antagonist; Cushing’s disease; Melanocortin 2 receptor (MC2R)