Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024):: Evaluation in vitro and in vivo

被引:147
作者
Kask, A
Mutulis, F
Muceniece, R
Pähkla, R
Mutule, I
Wikberg, JES
Rägo, L
Schiöth, HB
机构
[1] Uppsala Univ, Dept Pharmaceut Pharmacol, Ctr Biomed, S-75124 Uppsala, Sweden
[2] Tartu State Univ, Dept Pharmacol, EE-50090 Tartu, Estonia
[3] Inst Organ Synth, Pharmacol Lab, LV-1006 Riga, Latvia
关键词
D O I
10.1210/en.139.12.5006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (K-i = 0.29 nM) for the MC4 receptor. HS024 (cyclic [AcCys(3),Nle(4),Arg(5),D-Nal(7),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 l-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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页码:5006 / 5014
页数:9
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