title: Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo.
abstract: Several novel cyclic MSH analogs were synthesized, and their binding properties were tested on cells transiently expressing the human melanocortin-1 (MC1), MC3, MC4, and MC5 receptors. We discovered a novel substance (HS024) that showed about 20-fold selectivity and very high affinity (Ki = 0.29 nM) for the MC4 receptor. HS024 (cyclic [AcCys3,Nle4,Arg5,D-Nal7,Cys-NH2(11)]alpha-MSH-(3-11)) has a 29-membered atom ring structure that includes an Arg in position 5. HS024 was found to antagonize an alphaMSH-induced cAMP response in cells expressing the human MC1, MC3, MC4, and MC5 receptor DNAs. HS024 also caused a dose-dependent increase in food intake, with a maximum response (4-fold increase) at a 1-nmol dose injected intracerebroventricularly in free feeding rats. We also tested SHU9119, a previously described nonselective MC receptor antagonist, and found HS024 and SHU9119 to have similar potencies for increasing food intake, although SHU9119 appeared to induce more serious side-effects. HS024 increased the food intake of free feeding rats to levels comparable to those in food-deprived rats, indicating that blockade of the MC4 receptor is a highly effective way to increase feeding. Moreover, we tested the effects of intracerebroventricular injections of HS024 in elevated plus-maze and open-field experiments on rats. In these tests, HS024 did not appear to affect emotionality or locomotor activity, suggesting that the MC4 receptor does not mediate the anxiogenic-like and locomotor effects related to the melanocortic peptides.
authors.affiliation: Department of Pharmacology, University of Tartu, Estonia.
authors.forename: A
authors.initials: A
authors.lastname: Kask
authors.forename: F
authors.initials: F
authors.lastname: Mutulis
authors.forename: R
authors.initials: R
authors.lastname: Muceniece
authors.forename: R
authors.initials: R
authors.lastname: Pähkla
authors.forename: I
authors.initials: I
authors.lastname: Mutule
authors.forename: J E
authors.initials: JE
authors.lastname: Wikberg
authors.forename: L
authors.initials: L
authors.lastname: Rägo
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D019556:COS Cells / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009074:Melanocyte-Stimulating Hormones / Q000009:adverse effects / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; C116098:HS 024; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP