Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Discovery of novel melanocortin4 receptor selective MSH analogues. 963 Mar 46

We synthesised nine analogues of [Nle4,D-Phe7]alpha-MSH (melanocyte-stimulating hormone) (NDP) where (1) the N- or C-terminals were deleted or exchanged by those of beta- or gamma-MSH and (2) the core residues His6, Phe7, Arg8 and Trp9 were individually substituted by Glu6, beta-(2-naphthyl)-D-alanine (D-Nal7), Lys8 and His9, respectively. We tested these analogues in ligand binding assays with cells transiently expressing the human melanocortin MC1, MC3, MC4 and MC5 receptors. The results show that the N-terminal segment (Ser1-Tyr2-Ser3) of NDP was not important for binding to melanocortin MC1 and MC4 receptors whereas it affects binding to melanocortin MC3 and MC5 receptors. The C-terminal segment (Gly10-Lys11-Pro12-Val13) of NDP was clearly important for binding to all the four melanocortin receptor subtypes. The data indicate that the low affinity of gamma-MSH for the melanocortin MC4 receptor is due to its C-terminal (Asp10)-Arg11-Phe12). Substitution of D-Phe7 by D-Nal7 increased the affinity for the melanocortin MC4 receptor but not for the other melanocortin receptor subtypes. The other core residue substitutions lowered the affinity in a differentiated manner for each of the melanocortin receptors. These results are valuable for the molecular modelling and design of selective drugs for the melanocortin receptors.
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PMID:Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes. 967 Nov 18

Systemically administered alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits endotoxin (lipopolysaccharide; LPS)- or interleukin (IL)-1-induced fever and adrenocortical activation, but the sites of these actions and the mechanisms involved are unknown. The aims of this study were, first, to determine whether melanocortin receptors (MCR) located within the central nervous system mediate the suppressive effects of peripherally administered alpha-MSH on LPS-induced fever and activation of the pituitary-adrenal axis and, second, to determine whether systemic alpha-MSH suppresses the LPS-induced rise in plasma IL-6 levels, potentially contributing to its antipyretic effect. Male rats received Escherichia coli LPS (25 microg/kg ip). Core body temperatures (Tb) were determined hourly by radiotelemetry (0-8 h), and blood was withdrawn via venous catheters for plasma hormone immunoassays (0-2 h) and IL-6 bioassay (0-8 h). alpha-MSH (100 microg/kg ip) completely prevented the onset of LPS-induced fever during the first 3-4 h after LPS and suppressed fever throughout the next 4 h but did not affect Tb in afebrile rats treated with intraperitoneal saline rather than LPS. Intraperitoneal alpha-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and corticosterone (CS) levels. Intracerebroventricular injection of SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist, completely blocked the antipyretic effect of intraperitoneal alpha-MSH during the first 4 h after LPS but had no effect on alpha-MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered alpha-MSH during the early phase of fever is mediated by MCR within the brain. In contrast, the inhibition of LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal alpha-MSH appears to be mediated by a different mechanism(s), and these effects do not contribute to its antipyretic action.
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PMID:Systemic alpha-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release. 968 89

The melanocortin MC3 and MC4 receptors are the main melanocortin receptors expressed in brain. Of the endogenous melanocortins, gamma2-melanocortin stimulating hormone (MSH) selectively activates the melanocortin MC3 receptor, whereas alpha- and beta-MSH activate all melanocortin receptors. The aim was to gain an insight into the contribution of amino acids in positions 5 and 10 of melanocortins to the selectivity of [Nle4]Lys-gamma2-MSH for the melanocortin MC3 receptor versus the melanocortin MC4 receptor. Introduction of Asp10 into [Nle4]alpha-MSH as in [Nle4,Gly5,Asp10]alpha-MSH selectively increased the EC50 value for the melanocortin MC4 receptor. Conversely, removal of Asp10, as in [Nle4,Gly10]Lys-gamma2-MSH, selectively decreased the EC50 value for the melanocortin MC4 receptor. Thus, Asp10 in Lys-gamma2-MSH determined selectivity for the melanocortin MC3 receptor versus the melanocortin MC4 receptor.
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PMID:Asp10 in Lys-gamma2-MSH determines selective activation of the melanocortin MC3 receptor. 972 42

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.
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PMID:Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo. 983 40

The melanocortins form a family of pro-opiomelanocortin-derived peptides that have the melanocyte-stimulating hormone (MSH) core sequence, His-Phe-Arg-Trp, in common. Melanocortins have been described as having a variety of cardiovascular effects. We review here what is known about the sites and mechanisms of action of the melanocortins with respect to their effects on cardiovascular function, with special attention to the effects of the gamma-melanocyte-stimulating hormones (gamma-MSHs). This is done in the context of present knowledge about agonist selectivity and localisation of the five melanocortin receptor subtypes cloned so far. gamma2-MSH, its des-Gly12 analog (= gamma1-MSH) and Lys-gamma2-MSH are 5-10 times more potent than adrenocorticotropic hormone-(4-10)(ACTH-(4-10)) to induce a pressor and tachycardiac effect following intravenous administration. The Arg-Phe sequence near the C-terminal seems to be important for full in vivo intrinsic activity. Related peptides with a C-terminal extension with (gamma3-MSH) or without the Arg-Phe sequence (alpha-MSH, as well as the potent alpha-MSH analog, [Nle4,D-Phe7]alpha-MSH), are, however, devoid of these effects. In contrast, ACTH-(1-24) has a depressor effect combined with a tachycardiac effect, effects which are not dependent on the presence of the adrenals. Although the melanocortin MC3 receptor is the only melanocortin receptor subtype for which gamma2-MSH is selective, in vivo and in vitro structure-activity data indicate that it is not via this receptor that this peptide and related peptides exert either their pressor and tachycardiac effects or their extra- and intracranial blood flow increasing effect. We review evidence that the pressor and tachycardiac effects of the gamma-MSHs are due to an increase of sympathetic outflow to the vasculature and the heart, secondary to activation of centrally located receptors. These receptors are most likely localised in the anteroventral third ventricle (AV3V) region, a brain region situated outside the blood-brain barrier, and to which circulating peptides have access. These receptors might be melanocortin receptors of a subtype yet to be identified. Alternatively, they might be related to other receptors for which peptides with a C-terminal Arg-Phe sequence have affinity, such as the neuropeptide FF receptor and the recently discovered FMRFamide receptor. Melanocortin MC4 receptors and still unidentified receptors are part of the circuitry in the medulla oblongata which is involved in the depressor and bradycardiac effect of the melanocortins, probably via interference with autonomic outflow. Regarding the effects of the gamma-MSHs on cortical cerebral blood flow, it is not yet clear whether they involve activation of the sympathetic nervous system or activation of melanocortin receptors located on the cerebral vasculature. The depressor effect observed following intravenous administration of ACTH-(1-24) is thought to be due to activation of melanocortin MC2 receptors whose location may be within the peripheral vasculature. Melanocortins have been observed to improve cardiovascular function and survival time in experimental hemorrhagic shock in various species. Though ACTH-(1-24) is the most potent melanocortin in this model, alpha-MSH and [Nle4,D-Phe7]alpha-MSH and ACTH-(4-10) are quite effective as well. As ACTH-(4-10) is a rather weak agonist of all melanocortin receptors, it is difficult to determine via which of the melanocortin receptors the melanocortins bring about this effect. Research into the nature of the receptors involved in the various cardiovascular effects of the melanocortins would greatly benefit from the availability of selective melanocortin receptor antagonists.
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PMID:Melanocortins and cardiovascular regulation. 984 66

Although neurotrophic effects of alpha-melanocyte-stimulating hormone (alpha-MSH) are well established, the mechanism underlying these effects is unknown. To identify candidate components of the signaling system that may mediate these effects, in the present study rat spinal cord, dorsal root ganglia, sciatic nerve and soleus muscle were analysed for the expression of the neural MC3, MC4 and MC5 receptors and for the expression of the melanocortin precursor pro-opiomelanocortin (POMC). In rat lumbar spinal cord, the MC4 receptor was the only MC receptor subtype for which mRNA was detectable using RNAse protection assays. In situ binding studies using 125I-NDP-MSH, a synthetic alpha-MSH analogue, demonstrated MC receptor protein in the rat spinal cord, predominantly localised in substantia gelatinosa and area X, surrounding the central canal. Furthermore, POMC mRNA was demonstrated in rat spinal cord and dorsal root ganglia. These findings suggest a functional melanocortin system in the rat spinal cord, that might be involved in peripheral nerve repair. Regulation of POMC or MC receptor transcripts does not appear to be involved in the response to peripheral nerve crush in rats, since no change in mRNA expression patterns was detected after sciatic nerve crush, using quantitative RNAse protection assays. Nevertheless, subtle changes in melanocortin receptor binding did occur postsurgically in several regions of the spinal cord in both sham-operated and sciatic nerve-lesioned rats. The robust expression of MC receptor protein in spinal cord regions that are generally associated with nociception suggests a potentially broader involvement of endogenous melanocortins in spinal pathways which mediate the responses to peripheral injury, in addition to any direct melanocortin effects on sprouting and neurite outgrowth.
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PMID:Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. 987 83

Agouti-related protein (AGRP) is a naturally occurring antagonist of melanocortin action that is thought to play an important role in the hypothalamic control of feeding behavior. The exact mechanism of AGRP and Agouti protein action has been difficult to examine, in part because of difficulties in producing homogeneous forms of these molecules that can be used for direct binding assays. In this report we describe the application of chemical protein synthesis to the construction of two novel AGRP variants. Examination of the biological activity of the AGRP variants demonstrates that a truncated variant, human AGRP(87-132), a 46-amino acid variant based on the carboxyl-terminal cysteine-rich domain of AGRP, is equipotent to an 111-amino acid variant, mouse [Leu127Pro]AGRP (mature AGRP minus its signal sequence), in its ability to dose dependently inhibit alpha-MSH-generated cAMP generation at the cloned melanocortin receptors. Furthermore, deletion of the amino-terminal portion of the full-length variant did not alter the MCR subtype specificity of AGRP(87-132). Finally, iodination of human AGRP(87-132) provided a useful reagent with which the binding properties of AGRP could be analyzed. In both conventional and photoemulsion binding studies [125I]AGRP(87-132) was observed only to bind to cells expressing melanocortin receptors MC3R, MC4R, and MC5R. These results demonstrate that the residues critical for receptor binding, alpha-MSH inhibition, and melanocortin receptor subtype specificity are all located in the carboxyl terminus of the molecule. Because [Nle4, D-Phe7] (NDP)-MSH displaces the binding of [125I]AGRP(87-132) to MCRs and AGRP(87-132) displaces the binding of [125I]NDP-MSH, we conclude that these molecules bind in a competitive fashion to melanocortin receptors.
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PMID:Characterization of Agouti-related protein binding to melanocortin receptors. 989 20

The natural melanocortic peptides are known to exert a variety of effects after central administration. Recently, we discovered the first potent and selective substances for the MC4 receptor, i.e. HS964 and HS014. We found HS964 to be an antagonist for the MC1, MC3, MC4 and MC5 receptors in vitro. HS014 is an antagonist for the MC3 and MC4 receptors and a partial antagonist for the MC1 and MC5 receptors. We injected alpha-MSH and these substances, both intracerebroventricular (ICV) and in the ventral tegmental area (VTA) in rats and scored several behavioural effects. The results show that alpha-MSH caused intensive grooming which was antagonized by pre-treatment of both HS014 and HS964. The data give further support to the hypothesis that it is the MC4 receptor which mediates grooming in rodents. The grooming effects of alpha-MSH were more pronounced after intra-VTA administration compared to the ICV administration. Both alpha-MSH, HS014 and HS964 caused an increase in vertical activity of the rats after intra-VTA administration but not after ICV administration. Horizontal activity was virtually not affected by the administration of the peptides. The data indicate that the neural MC3 and MC4 receptors are not likely to be an important mediators of locomotor activity in rats.
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PMID:Evaluation of behavioural effects of neural melanocortin receptor antagonists injected ICV and in VTA in rats. 992 Apr 57

1. We designed and synthesized several novel cyclic MSH analogues and tested their affinities for cells expressing the MC1, MC3, MC4 and MC5 receptors. 2. One of the substances HS028 (cyclic [AcCys11, dichloro-D-phenylalanine14, Cys18, Asp-NH2(22)]-beta-MSH11-22) showed high affinity (Ki of 0.95nM) and high (80 fold) MC4 receptor selectivity over the MC3 receptor. HS028 thus shows both higher affinity and higher selectivity for the MC4 receptor compared to the earlier first described MC4 receptor selective substance HS014. 3. HS028 antagonised a alpha-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 significantly increased both food intake and body weight in a dose dependent manner without tachyphylaxis for a period of 7 days. 5. This is the first 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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PMID:Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist. 1005 Nov 17


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