{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:37:36Z","timestamp":1760240256287,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,13]],"date-time":"2019-04-13T00:00:00Z","timestamp":1555113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK091906","F32DK108402"],"award-info":[{"award-number":["R01DK091906","F32DK108402"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Minnesota, Wallin Neuroscience Discovery Fund Award","award":["2017"],"award-info":[{"award-number":["2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The five melanocortin receptors (MC1R\u2013MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist\/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.<\/jats:p>","DOI":"10.3390\/molecules24081463","type":"journal-article","created":{"date-parts":[[2019,4,15]],"date-time":"2019-04-15T11:15:58Z","timestamp":1555326958000},"page":"1463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structure\u2013Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands"],"prefix":"10.3390","volume":"24","author":[{"given":"Katherine N.","family":"Schlasner","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry &amp; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8715-6010","authenticated-orcid":false,"given":"Mark D.","family":"Ericson","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry &amp; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Skye R.","family":"Doering","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry &amp; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie T.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry &amp; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Weinrich","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry &amp; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6783-5972","authenticated-orcid":false,"given":"Carrie","family":"Haskell-Luevano","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry &amp; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1006\/bbrc.1993.2125","article-title":"Molecular cloning of a novel human melanocortin receptor","volume":"195","author":"Chhajlani","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/0014-5793(92)80820-7","article-title":"Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA","volume":"309","author":"Chhajlani","year":"1992","journal-title":"FEBS Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1126\/science.1325670","article-title":"The cloning of a family of genes that encode the melanocortin receptors","volume":"257","author":"Mountjoy","year":"1992","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8856","DOI":"10.1073\/pnas.90.19.8856","article-title":"Identification of a receptor for \u03b3 melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system","volume":"90","author":"Mountjoy","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8246","DOI":"10.1016\/S0021-9258(18)53088-X","article-title":"Molecular cloning of a novel melanocortin receptor","volume":"268","author":"Gantz","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15174","DOI":"10.1016\/S0021-9258(18)82452-8","article-title":"Molecular cloning, expression, and gene localization of a fourth melanocortin receptor","volume":"268","author":"Gantz","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1006\/bbrc.1994.1580","article-title":"Molecular cloning, expression, and characterization of a fifth melanocortin receptor","volume":"200","author":"Gantz","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1006\/bbrc.1994.1550","article-title":"Molecular cloning and characterization of the rat fifth melanocortin receptor","volume":"200","author":"Griffon","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/S0021-9258(19)77372-4","article-title":"The activation of adrenal phosphorylase by the adreno-corticotropic hormone","volume":"233","author":"Haynes","year":"1958","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/0024-3205(96)00370-0","article-title":"Major pharmacological distinction of the ACTH receptor from other melanocortin receptors","volume":"59","author":"Schioth","year":"1996","journal-title":"Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1210\/endo.141.9.7791","article-title":"A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse","volume":"141","author":"Butler","year":"2000","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/79254","article-title":"Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass","volume":"26","author":"Chen","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0092-8674(00)81865-6","article-title":"Targeted disruption of the melanocortin-4 receptor results in obesity in mice","volume":"88","author":"Huszar","year":"1997","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/385165a0","article-title":"Role of melanocortinergic neurons in feeding and the agouti obesity syndrome","volume":"385","author":"Fan","year":"1997","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/S0092-8674(00)80467-5","article-title":"Exocrine gland dysfunction in MC5-R-deficient mice: Evidence for coordinated regulation of exocrine gland function by melanocortin peptides","volume":"91","author":"Chen","year":"1997","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/278423a0","article-title":"Nucleotide sequence of cloned cDNA for bovine corticotropin-\u03b2-lipotropin precursor","volume":"278","author":"Nakanishi","year":"1979","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/edrv-1-1-1","article-title":"Structure and biosynthesis of pro-adrenocorticotropin\/endorphin and related peptides","volume":"1","author":"Eipper","year":"1980","journal-title":"Endocr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1210\/edrv-9-1-159","article-title":"Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues","volume":"9","author":"Smith","year":"1988","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1021\/jm00394a033","article-title":"\u03b1-Melanotropin: The minimal active sequence in the frog-skin bioassay","volume":"30","author":"Hruby","year":"1987","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0016-6480(89)90066-X","article-title":"\u03b1-Melanotropin: The minimal active sequence in the lizard skin bioassay","volume":"73","author":"Castrucci","year":"1989","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1021\/bi971913h","article-title":"Melanocortin receptor binding determinants in the agouti protein","volume":"37","author":"Kiefer","year":"1998","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1021\/bi9815602","article-title":"Molecular interaction of agouti protein and agouti-related protein with human melanocortin receptors","volume":"38","author":"Tota","year":"1999","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ejphar.2010.10.101","article-title":"Implication of the melanocortin-3 receptor in the regulation of food intake","volume":"660","author":"Irani","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"R1667","DOI":"10.1152\/ajpregu.00562.2009","article-title":"Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors","volume":"298","author":"Atalayer","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.pbb.2010.03.008","article-title":"Effect of serotonergic anorectics on food intake and induction of Fos in brain of mice with disruption of melanocortin 3 and\/or 4 receptors","volume":"97","author":"Rowland","year":"2010","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1016\/j.peptides.2010.08.016","article-title":"Effect of MTII on food intake and brain c-Fos in melanocortin-3, melanocortin-4, and double MC3 and MC4 receptor knockout mice","volume":"31","author":"Rowland","year":"2010","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0167-0115(98)00127-X","article-title":"Central injection in rats of \u03b1-melanocyte-stimulating hormone analog: Effects on food intake and brain Fos","volume":"78","author":"Brown","year":"1998","journal-title":"Regul. Pept."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.2337\/diabetes.48.10.2028","article-title":"Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action","volume":"48","author":"Ebihara","year":"1999","journal-title":"Diabetes"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/B978-0-12-386933-3.00005-4","article-title":"Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis","volume":"114","author":"Hinney","year":"2013","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMoa0803085","article-title":"Modulation of blood pressure by central melanocortinergic pathways","volume":"360","author":"Greenfield","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1016\/0024-3205(96)00160-9","article-title":"Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study","volume":"58","author":"Dorr","year":"1996","journal-title":"Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1021\/jm9017866","article-title":"Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans","volume":"53","author":"Lansdell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1016\/j.peptides.2005.01.023","article-title":"Discovery that a melanocortin regulates sexual functions in male and female humans","volume":"26","author":"Hadley","year":"2005","journal-title":"Peptides"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1056\/NEJMoa1512693","article-title":"Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist","volume":"375","author":"Kuhnen","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/s41591-018-0015-9","article-title":"MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency","volume":"24","author":"Clement","year":"2018","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1097\/01.hjh.0000249702.49854.fa","article-title":"Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones","volume":"24","author":"Ni","year":"2006","journal-title":"J. Hypertens."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0014-2999(02)02479-2","article-title":"Activation of melanocortin MC4 receptors increases erectile activity in rats ex copula","volume":"454","author":"Martin","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11381","DOI":"10.1073\/pnas.172378699","article-title":"A role for the melanocortin 4 receptor in sexual function","volume":"99","author":"Martin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/bs.pmbts.2016.01.002","article-title":"Mutations in melanocortin-3 receptor gene and human obesity","volume":"140","author":"Yang","year":"2016","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1021\/acs.jmedchem.7b00301","article-title":"Discovery of mixed pharmacology melanocortin-3 agonists and melanocortin-4 receptor tetrapeptide antagonist compounds (TACOs) based on the sequence Ac-Xaa(1)-Arg-(pI)DPhe-Xaa(4)-NH2","volume":"60","author":"Doering","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1021\/acs.jmedchem.9b00053","article-title":"Discovery of polypharmacological melanocortin-3 and -4 receptor probes and identification of a 100-fold selective nM MC3R agonist versus a \u00b5M MC4R partial agonist","volume":"62","author":"Fleming","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5585","DOI":"10.1021\/jm800291b","article-title":"Melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) modified at the para position of the benzyl side chain (DPhe): Importance for mouse melanocortin-3 receptor agonist versus antagonist activity","volume":"51","author":"Proneth","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1021\/jm010524p","article-title":"Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 at the mouse melanocortin receptors: Part 2 modifications at the Phe position","volume":"45","author":"Holder","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1021\/ja00722a043","article-title":"9-Fluorenylmethoxycarbonyl function, a new base-sensitive amino-protecting group","volume":"92","author":"Carpino","year":"1970","journal-title":"J. Am. Chem. Soc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1021\/jo00795a005","article-title":"The 9-fluorenylmethoxycarbonyl amino-protecting group","volume":"37","author":"Carpino","year":"1972","journal-title":"J. Org. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1006\/abio.1995.1235","article-title":"A colorimetric assay for measuring activation of Gs- and Gq-coupled signaling pathways","volume":"226","author":"Chen","year":"1995","journal-title":"Anal. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5306","DOI":"10.1016\/j.bmcl.2015.09.046","article-title":"A fragment of the Escherichia coli ClpB heat-shock protein is a micromolar melanocortin 1 receptor agonist","volume":"25","author":"Ericson","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5708","DOI":"10.1016\/j.bmcl.2015.10.095","article-title":"Microwave-assisted solid-phase synthesis of side-chain to side-chain lactam-bridge cyclic peptides","volume":"25","author":"Tala","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1021\/acsmedchemlett.5b00053","article-title":"Synthesis and pharmacology of \u03b1\/\u03b23-peptides based on the melanocortin agonist Ac-His-DPhe-Arg-Trp-NH2 sequence","volume":"6","author":"Singh","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5754","DOI":"10.1073\/pnas.77.10.5754","article-title":"4-Norleucine, 7-D-phenylalanine-\u03b1-melanocyte-stimulating hormone\u2014A highly potent \u03b1-melanotropin with ultralong biological-activity","volume":"77","author":"Sawyer","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1021\/jm010061n","article-title":"Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors","volume":"44","author":"Holder","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.1476-5381.1947.tb00336.x","article-title":"pA, a new scale for the measurement of drug antagonism","volume":"2","author":"Schild","year":"1947","journal-title":"Br. J. Pharmacol. Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.ejmech.2018.04.021","article-title":"Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation","volume":"151","author":"Haghighi","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0003-2697(70)90146-6","article-title":"Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides","volume":"34","author":"Kaiser","year":"1970","journal-title":"Anal. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"763","DOI":"10.3891\/acta.chem.scand.33b-0763","article-title":"Qualitative test for monitoring coupling completeness in solid-phase peptide-synthesis using chloranil","volume":"33","author":"Christensen","year":"1979","journal-title":"Acta Chem. Scand. Ser. B"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1021\/acs.jmedchem.5b01894","article-title":"An in vitro and in vivo investigation of bivalent ligands that display preferential binding and functional activity for different melanocortin receptor homodimers","volume":"59","author":"Lensing","year":"2016","journal-title":"J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/8\/1463\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:45:11Z","timestamp":1760186711000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/8\/1463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,13]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["molecules24081463"],"URL":"https:\/\/doi.org\/10.3390\/molecules24081463","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2019,4,13]]}}}