Synthesis and Pharmacology of α/β(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence.

The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β(3)-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β(3)hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.

[1]  Manuela Grimaldi,et al.  1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity , 2014, Journal of medicinal chemistry.

[2]  C. Haskell-Luevano,et al.  Melanocortin ligands: 30 years of structure–activity relationship (SAR) studies , 2004, Medicinal research reviews.

[3]  M. Mortrud,et al.  Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. , 1994, Molecular endocrinology.

[4]  D. Seebach,et al.  On the Biodegradation of β‐Peptides , 2002 .

[5]  R. Mains,et al.  Structure and biosynthesis of pro-adrenocorticotropin/endorphin and related peptides. , 1980, Endocrine reviews.

[6]  D. Seebach,et al.  The outstanding biological stability of beta- and gamma-peptides toward proteolytic enzymes: an in vitro investigation with fifteen peptidases. , 2001, Chembiochem : a European journal of chemical biology.

[7]  V. Hruby,et al.  Truncation studies of α-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity , 1996, Peptides.

[8]  V J Hruby,et al.  alpha-Melanotropin: the minimal active sequence in the frog skin bioassay. , 1987, Journal of medicinal chemistry.

[9]  U. Samanta,et al.  Packing of aromatic rings against tryptophan residues in proteins. , 1999, Acta crystallographica. Section D, Biological crystallography.

[10]  R. Cone,et al.  Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice , 1997, Cell.

[11]  A. Edison,et al.  Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR. , 2011, Journal of medicinal chemistry.

[12]  W. Millard,et al.  Implication of the melanocortin-3 receptor in the regulation of food intake. , 2011, European journal of pharmacology.

[13]  S. Salvadori,et al.  Structural and biological exploration of phe(3)-phe(4)-modified endomorphin-2 peptidomimetics. , 2013, ACS medicinal chemistry letters.

[14]  S. Mammi,et al.  Conformational and biological characterization of human parathyroid hormone hPTH(1–34) analogues containing β‐amino acid residues in positions 17–19 , 2003, Biopolymers.

[15]  T K Sawyer,et al.  Alpha-melanotropin: the minimal active sequence in the lizard skin bioassay. , 1989, General and comparative endocrinology.

[16]  Ximena Opitz-Araya,et al.  Exocrine Gland Dysfunction in MC5-R-Deficient Mice: Evidence for Coordinated Regulation of Exocrine Gland Function by Melanocortin Peptides , 1997, Cell.

[17]  James Gardiner,et al.  Beta-peptidic peptidomimetics. , 2008, Accounts of chemical research.

[18]  V J Hruby,et al.  Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. , 1997, Journal of medicinal chemistry.

[19]  D. Hoyer,et al.  β2/β3-di- and α/β3-tetrapeptide derivatives as potent agonists at somatostatin sst4 receptors , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[20]  M. Mortrud,et al.  The cloning of a family of genes that encode the melanocortin receptors. , 1992, Science.

[21]  A. Levine,et al.  Synthesis, Biophysical, and Pharmacological Evaluation of the Melanocortin Agonist AST3-88: Modifications of Peptide Backbone at Trp 7 Position Lead to a Potent, Selective, and Stable Ligand of the Melanocortin 4 Receptor (MC4R) , 2014, ACS chemical neuroscience.

[22]  C. Haskell-Luevano,et al.  Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. , 2001, Journal of medicinal chemistry.

[23]  S. Watson,et al.  Molecular cloning of a novel melanocortin receptor. , 1993, The Journal of biological chemistry.

[24]  A. Glättli,et al.  Helices and other secondary structures of beta- and gamma-peptides. , 2006, Biopolymers.

[25]  R. Cone,et al.  A Unique Metalolic Sysdrone Causes Obesity in the Melanocortin-3 Receptor-Deficient Mouse. , 2000, Endocrinology.

[26]  R. Cone,et al.  A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. , 2000, Endocrinology.

[27]  Yue Feng,et al.  Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass , 2000, Nature Genetics.

[28]  D. Seebach,et al.  On the biodegradation of beta-peptides. , 2002, Chembiochem : a European journal of chemical biology.

[29]  D. Hoyer,et al.  Beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide derivatives as potent agonists at somatostatin sst(4) receptors. , 2003, Naunyn-Schmiedeberg's archives of pharmacology.

[30]  M. Mortrud,et al.  Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Seebach,et al.  The Outstanding Biological Stability of β‐ and γ‐Peptides toward Proteolytic Enzymes: An In Vitro Investigation with Fifteen Peptidases , 2001 .

[32]  J. Wikberg,et al.  Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA , 1992, FEBS letters.

[33]  Victor J. Hruby,et al.  Role of melanocortinergic neurons in feeding and the agouti obesity syndrome , 1997, Nature.

[34]  S. Watson,et al.  Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. , 1993, The Journal of biological chemistry.

[35]  A. Glättli,et al.  Helices and other secondary structures of β‐ and γ‐peptides , 2006 .

[36]  Y. Konda,et al.  Molecular cloning, expression, and characterization of a fifth melanocortin receptor. , 1994, Biochemical and biophysical research communications.

[37]  V. Hruby,et al.  Biological active analogues of the opioid peptide biphalin: mixed α/β(3)-peptides. , 2013, Journal of medicinal chemistry.