HS 014

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1beta administration.[Pubmed:18082228]

Neuropharmacology. 2008 Mar;54(3):509-20.

Loss of appetite and cachexia is an obstacle in the treatment of chronic infection and cancer. Proinflammatory cytokines released from activated immune cells and acting in the central nervous system (CNS) are prime candidates for mediating these metabolic changes, potentially affecting both energy intake as well as energy expenditure. The effect of intravenous administration of two proinflammatory cytokines, interleukin (IL)-1beta (15 microg/kg) and tumor necrosis factor (TNF)-alpha (10 microg/kg), on food and water intake, locomotor activity, oxygen consumption (VO2), and respiratory exchange ratio (RER) was evaluated. The two cytokines elicited a comparable decrease in food intake and activated similar numbers of cells in the paraventricular nucleus of the hypothalamus (PVH), a region that plays a critical role in the regulation of appetite and metabolism (determined via expression of the immediate early gene, c-fos). However, only IL-1beta reduced locomotion and RER, and increased VO2, while TNF-alpha was without effect. To examine the role of the melanocortins in mediating IL-1beta- induced metabolic changes, animals were pretreated centrally with a melanocortin receptor antagonist, HS014. Pretreatment with HS014 blocked the effect of IL-1beta on food intake and RER at later time points (beyond 8 h post injection), as well as the hypoactivity and increased metabolic rate. Further, HS014 blocked the induction of Fos-ir in the PVH. These data highlight the importance of the melanocortin system, particularly within the PVH, in mediating a broad range of metabolic responses to IL-1beta.

Melanocortin receptor agonists and antagonists modulate nociceptive sensitivity in the mouse formalin test.[Pubmed:14660013]

Eur J Pharmacol. 2003 Dec 15;482(1-3):127-32.

A number of studies suggest the involvement of melanocortins in nociception, and although the mechanism through which this occurs is still unknown, experimental evidence would suggest an involvement of melanocortin MC(4) receptors. We investigated the effect of melanocortin receptor agonist and antagonists on nociceptive behaviour induced by formalin in the mouse. The intrathecal injection of the melanocortin receptor agonist MTII ([Ac-Nle(4),Asp(5),D-Phe(7),Lys(10)]cyclo-alpha-MSH-(4-10) amide) (5 nmol; P<0.05) significantly increased nociception in both phases of the formalin test, whereas the synthetic melanocortin receptor antagonists, SHU9119 ([Ac-Nle(4),Asp(5),D-2-Nal(7),Lys(10)]cyclo-alpha-MSH-(4-10) amide) (5 nmol), HS014 ([Ac-Cys(11),D-2-Nal(14),Cys(18)]beta-MSH-(11-22)amide) (5 nmol), and JKC-363 (cyclic [Mpr(11),D-Nal(14),Cys(18),Asp(22)-NH(2)]beta-MSH-11-22)) (5 nmol), and the endogenous receptor antagonist Agouti-related protein (AgRP) (1.5 nmol) were effective in reducing nociception in the late phase of the formalin test (50-60% of reduction in licking/flinching response; P<0.05). The present findings further support the involvement of the melanocortin system in the control of nociception. Moreover, considering that melanocortin MC(4) receptors are the only melanocortin subtype receptors present in the spinal cord, we can assume that the activity of the peptides in the formalin model is mediated through melanocortin MC(4) receptors.

Discovery of novel melanocortin4 receptor selective MSH analogues.[Pubmed:9630346]

Br J Pharmacol. 1998 May;124(1):75-82.

1. We synthesized a novel series of cyclic melanocyte stimulating hormone (MSH) analogues and tested their binding properties on cells transiently expressing the human melanocortin1 (MC1), MC3, MC4 and MC5 receptors. 2. We discovered that compounds with 26 membered rings of [Cys4,D-Nal7,Cys11]alpha-MSH(4-11) displayed specific MC4 receptor selectivity. The preference order of the different MC receptor subtypes for the novel [Cys4D-Nal7Cys11]alpha-MSH(4-11) analogues are distinct from all other known MSH analogues, particularly as they bind the MC4 receptor with high and the MC1 receptor with low relative affinities. 3. HS964 and HS014 have 12 and 17 fold MC4/MC3 receptor selectivity, respectively, which is much higher than for the previously described cyclic lactam and [Cys4,Cys10]alpha-MSH analogues SHU9119 and HS9510. 4. HS964 is the first substance showing higher affinity for the MC5 receptor than the MC1 receptor. 5. HS014, which was the most potent and selective MC4 receptor ligand (Ki 3.2 nM, which is approximately 300 fold higher affinity than for alpha-MSH), was also demonstrated to antagonize alpha-MSH stimulation of cyclic AMP in MC4 receptor transfected cells. 6. We found that a compound with a 29 membered ring of [Cys3,Nle10,D-Nal7,Cys11]alpha-MSH(3-11) (HS010) had the highest affinity for the MC3 receptor. 7. This is the first study to describe ligands that are truly MC4 selective and a ligand having a high affinity for the MC3 receptor. The novel compounds may be of use in clarifying the physiological roles of the MC3, MC4 and MC5 receptors.