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

We determined the binding affinities of the MSH analogues MSH-B, HP-228 and 153N-6 and of the enkephalin analogue GHRP-6 on a single eukaryotic cell line transiently expressing the human MC1, MC3, MC4 and MC5 receptors. Moreover, we tested the binding and cAMP response of MSH-B in comparison with alpha-MSH on murine B16 melanoma cells. Our results indicate that MSH-B has a potency similar to that of alpha-MSH and that these two peptides induce similar cAMP responses in murine B16 melanoma cells. HP-228 has its highest affinity for the MC1 receptor. For the other receptors, it has slightly higher affinity for the MC5 receptor than for the MC3 and MC4 receptors. 153N-6 was found to be selective for the MC1 receptor. GHRP-6 was found to bind to the MC1 and the MC5 receptors despite its low structural homology with alpha-MSH. [D-Lys3]GHRP-6 bound to all the four MC receptors with similar affinities. The structurally related Met-enkephalin and the functionally related GHRH, as well as LHRH and somatostatin-14 did not bind to these MC receptors. The low affinity of the GH-releasing/enkephalin peptides may indicate that they do not interact with the MC receptors at pharmacologically relevant concentrations.
 ...
PMID:Characterization of the binding of MSH-B, HB-228, GHRP-6 and 153N-6 to the human melanocortin receptor subtypes. 957 23

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.
 ...
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

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.
 ...
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.
 ...
PMID:Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist. 1005 Nov 17

A tripeptoid library was synthesized using 69 different primary amines in initially 69 individual reactions by the mix and split approach. The resulting library consisted of 328,509 (69(3)) single compounds, divided in 69 subpools each containing 4,761 entities. The 69 subpools were tested in two binding assays, one for alpha-MSH (alpha-melanotropin) and one for GRP (gastrin-releasing peptide)/bombesin. The sublibraries with the highest affinity to the MSH receptor (i.e. melanocortin type 1 or MC1 receptor) and, respectively, the GRP-preferring bombesin receptor were identified by an iterative process. Individual tripeptoids with good binding activity were resynthesized, analyzed and their dissociation constants and biological activity determined. The KD of the most potent MC1 receptor ligand was 1.58 mumol/l and that of the GRP-preferring bombesin receptor 3.40 mumol/l. Extension of this latter tripeptoid structure whose KD value increased to 280 nmol/l. A similar increase in activity was not observed with the most potent MSH tripeptoid ligand when extended by one residue, but a compound suitable for radioiodination and lacking the N-terminal amino group had a slightly higher binding activity than the tripeptoids (KD approximately 850 nmol/l). These results demonstrate that testing a peptoid library containing 328,509 single compounds led to the successful identification of new ligands for both the MC1 receptor as well as the GRP-preferring bombesin receptor.
 ...
PMID:A combinatorial peptoid library for the identification of novel MSH and GRP/bombesin receptor ligands. 1007 77

Desacetyl-alpha-MSH is more abundant than alpha-MSH in the brain, the fetus, human blood, and amniotic fluid, but there is little information on its ability to interact with melanocortin receptors. The aim of this study is to compare and contrast the ability of desacetyl-alpha-MSH and alpha-MSH to couple melanocortin receptors stably expressed in HEK293 cells, to the protein kinase A (PKA) signaling pathway. Desacetyl-alpha-MSH activated mouse MC1, MC3, MC4 and MC5 receptors with EC50s = 0.13, 0.96, 0.53, and 0.84 nM, and alpha-MSH activated these receptors with EC50s = 0.17, 0.88, 1.05, and 1.34 nM, respectively. Mouse agouti protein competitively antagonized alpha-MSH and desacetyl-alpha-MSH coupling to the MC1-R similarly. In contrast, mouse agouti protein antagonized desacetyl-alpha-MSH much more effectively and potently than alpha-MSH coupling the MC4-R to the PKA signaling pathway. Furthermore, mouse agouti protein (10 nM) significantly reduced (1.4-fold) the maximum response of mMC4-R to desacetyl-alpha-MSH and 100 nM mouse agouti significantly increased (4.8-fold) the EC50. Minimal antagonism of alpha-MSH coupling mMC4-R to the PKA signaling pathway was observed with 10 nM mouse agouti, whereas both 50 and 100 nM mouse agouti appeared to reduce the maximum reponse (1.1- and 1.3-fold, respectively) and increase the EC50 (2.5- and 3.4-fold respectively). Mouse agouti protein did not significantly antagonize either alpha-MSH or desacetyl-alpha-MSH coupling mouse MC3 and MC5 receptors. Understanding the similarities and differences in activation of melanocortin receptors by desacetyl-alpha-MSH and alpha-MSH will contribute to delineating the functional roles for these endogenous melanocortin peptides.
 ...
PMID:Agouti antagonism of melanocortin-4 receptor: greater effect with desacetyl-alpha-melanocyte-stimulating hormone (MSH) than with alpha-MSH. 1021 68

The structural and dynamical features of the hormone alpha-MSH in solution have been examined over a 100 ns time scale by using free energy molecular mechanics models at room temperature. The free energy surface has been modeled using methods from integral equation theory and the dynamics by the Langevin equation. A modification of the accessible surface area friction drag model was used to calculate the atomic friction coefficients. The molecule shows a stable beta-turn conformation in the message region and a close interaction between the side chains of His6, Phe7, and Trp9. A salt bridge between Glu5 and Arg8 was found not to be a preferred interaction, whereas a Glu5 and Lys11 salt bridge was not sampled, presumably due to relatively high free energy barriers. The message region was more conformationally rigid than the N-terminal region. Several structural features observed here agree well with experimental results. The conformational features suggest a receptor-hormone interaction model where the hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion of the MC1 receptor. Also, the positively charged side chain of Arg8 and the imidazole side chain of His6 may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops.
 ...
PMID:Structure and dynamics of alpha-MSH using DRISM integral equation theory and stochastic dynamics. 1039 88

The melanocortin 1 receptor is a G-protein-coupled receptor that acts as a control point for control of the eumelanin/phaeomelanin ratio in mouse hair. MC1 receptor loss of function mutations lead to an increase in the ratio of phaeomelanin/eumelanin in many mammals resulting in yellow or red coat colours. We have previously shown that several common point mutations in the human MC1 receptor are overrepresented in North European redheads and in individuals with pale skin. In order to determine the functional significance of these changes we have carried out transfection and binding studies. Expression of the Val60Leu, Arg142His, Arg151Cys, Arg160Trp, and Asp294His receptors in COS 1 cells revealed that these receptors were unable to stimulate cAMP production as strongly as the wild type receptor in response to alpha-melanocyte-stimulating hormone stimulation. None of the mutant receptors displayed complete loss of alphaMSH binding, with only the Arg142His and Asp294His displaying a slight reduction in binding affinity.
 ...
PMID:Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair. 1040 94

We tested the endogenous tripeptide TRH (thyrotropin releasing hormone) ability to bind to MC (melanocortin) receptor subtypes. We discovered that TRH binds to the human MCI receptor expressed in COS cells and to murine B16 melanoma cells with 5790+/-1010 nM and 6370+/-1260 nM Ki's, respectively. TRH did not bind to the human MC3, MC4 or MC5 receptor subtypes. Moreover, TRH also stimulated cAMP production in murine B16 melanoma cells reaching the same maximum level of cAMP as found for alpha-MSH. However, several analogues of TRH, including TRH-OH, TRH-Gly-NH2 and other analogues, where each of the three amino acid residues in TRH had been exchanged by a related residue, did not bind to any of the MC receptors tested in this study. C(alpha) atoms of molecular models of TRH and the core of a MSH peptide were aligned with r.m.s. of 0.01 A. Moreover, TRH could be docked into a binding pocket of a molecular model of the MC1 receptor at only a little higher energy than a short cyclic MSH peptide. The data indicate a similarity in the mode of TRH and MSH activation of the MCI receptor.
 ...
PMID:Thyrotropin releasing hormone (TRH) selectively binds and activates the melanocortin 1 receptor. 1044

A conformational search for the most probable structures of the hormone alpha-MSH in aqueous solution was performed in order to help determine the structural features necessary for biological activity. The free-energy surface was modeled using methods from integral equation theory, and high-temperature molecular dynamics was used to enhance conformational sampling. Families of low free-energy structures have been found. The minimum energy structure shows a stable beta-turn conformation in the putative message region that is stabilized by a salt bridge between Glu5 and Lys11. The orientation of the side chains reflects the amphiphilic nature of the peptide, and a close interaction between the side chains of the His6, Phe7 and Trp9 was observed. Several structural features observed in the minimum energy structure agree well with experimental results. The conformational features led to a hypothesis of a receptor-hormone interaction model in which the hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion of the human melanocortin (MC1) receptor. Also, the positively charged side chain of Arg8 and the imidazole side chain of His6 may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops.
 ...
PMID:Modeling of alpha-MSH conformations with implicit solvent. 1056 5


<< Previous 1 2 3 4 5 6 Next >>