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Endocrinology Vol. 139, No. 12 5006-5014
Copyright © 1998 by The Endocrine Society

ARTICLES

Discovery of a Novel Superpotent and Selective Melanocortin-4 Receptor Antagonist (HS024): Evaluation in Vitro and in Vivo1

Ants Kask, Felikss Mutulis, Ruta Muceniece, Rein Pähkla, Ilze Mutule, Jarl E. S. Wikberg, Lembit Rägo and Helgi B. Schiöth

Department of Pharmacology, University of Tartu (A.K., R.P., L.R.), Ulikooli 18, 50090 Tartu, Estonia; the Department of Medicinal Chemistry (F.M., I.M.) and the Laboratory of Pharmacology (R.M.), Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia; and the Department of Pharmaceutical Pharmacology, Uppsala University (F.M., R.M., I.M., J.E.S.W., H.B.S.), 751 24 Uppsala, Sweden

Address all correspondence and requests for reprints to: Dr. Helgi B. Schiöth, Department of Pharmaceutical Pharmacology, Biomedical Center, Box 591, 751 24 Uppsala, Sweden. E-mail: helgis{at}bmc.uu.se

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-NH211]{alpha}-MSH-(3–11)) has a 29-membered atom ring structure that includes an Arg in position 5. HS024 was found to antagonize an {alpha}MSH-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.




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