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1 We designed and synthesized several novel cyclic MSH analogues and tested their a nities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2 One of the substances HS028 (cyclic [AcCys 11 , dichloro-D-phenylalanine 14 , Cys 18 , Asp-NH 2 22 ]-b-MSH 11 ± 22 ) showed high a nity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher a nity and higher selectivity for the MC4 receptor compared to the earlier ®rst described MC4 receptor selective substance HS014. 3 HS028 antagonised a a-MSH induced increase in cyclic AMP production in transfected cells expressing the MC3 and MC4 receptors, whereas it seemed to be a partial agonist for the MC1 and MC5 receptors. 4 Chronic intracerebroventricularly (i.c.v.) administration of HS028 by osmotic minipumps signi®cantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5 This is the ®rst report demonstrating that an MC4 receptor antagonist can increase food intake and body weight during chronic administration providing further evidence that the MC4 receptor is an important mediator of long term weight homeostasis.

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The central melanocortin system is involved in the regulation of food intake and body weight. In this study, we investigated the effect of a 4-week intracerebroventricular infusion of the melanocortin receptor agonist MT-II and the selective melanocortin-4 receptor antagonist HS024 on food intake and body weight homeostasis. The MT-IItreated rats ate less and lost considerably more weight than the control rats during the first week of treatment. During the second and third week, they gained weight and, by the end of the treatment period, the weight gain was similar to that of the control rats. The HS024 treatment caused hyperphagia and development of obesity during the entire period. Extensive accumulations of fat and a sixfold increase in leptin levels were observed in the HS024-treated rats, as compared with controls, after the 4-week period. Food conversion ratio, defined as body weight increase relative to weight of ingested food, was clearly increased in the HS024-treated rats, while it was lowered in the MT-II-treated rats compared with controls. The effect on food conversion ratio was transient, being greatest for both experimental groups during the first week and it was then attenuated to reach the level of controls at the end of the study. The results suggest that long-term injection of exogenous melanocortin receptor active substances may have an important transient effect on food conversion.