{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:13:27Z","timestamp":1760242407104,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2017,7,15]],"date-time":"2017-07-15T00:00:00Z","timestamp":1500076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish MINECO","award":["CTQ2014-52633-P"],"award-info":[{"award-number":["CTQ2014-52633-P"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["UID\/Multi\/04349\/2013"],"award-info":[{"award-number":["UID\/Multi\/04349\/2013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Linear and cyclic analogues of the \u03b1-melanocyte stimulating hormone (\u03b1-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of \u03b1-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for \u03b1-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric \u03b1-MSH analogues, c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH2 (CycN-K6) and c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH2 (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by 1H and 13C NMR. These results were compared to those of the previously reported analogue c[S-NO2-C6H3-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH2 (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 \u00b1 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 \u00b1 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC50 = 1770 \u00b1 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle\u2019s side chains are favorably positioned for receptor interaction.<\/jats:p>","DOI":"10.3390\/molecules22071189","type":"journal-article","created":{"date-parts":[[2017,7,18]],"date-time":"2017-07-18T03:45:16Z","timestamp":1500349516000},"page":"1189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor"],"prefix":"10.3390","volume":"22","author":[{"given":"Maur\u00edcio","family":"Morais","sequence":"first","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela LRS, Portugal"},{"name":"Division of Imaging Sciences and Biomedical Engineering, King\u2019s College London, 4th Floor Lambeth Wing, St Thomas\u2019 Hospital, London SE1 7EH, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9141-2750","authenticated-orcid":false,"given":"H\u00e9ctor","family":"Zamora-Carreras","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica F\u00edsica Rocasolano (IQFR), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Serrano 119, 28006 Madrid, Spain"}]},{"given":"Paula","family":"Raposinho","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela LRS, Portugal"}]},{"given":"Maria","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela LRS, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4390-6972","authenticated-orcid":false,"given":"David","family":"Pantoja-Uceda","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica F\u00edsica Rocasolano (IQFR), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Serrano 119, 28006 Madrid, Spain"}]},{"given":"Jo\u00e3o","family":"Correia","sequence":"additional","affiliation":[{"name":"Centro de Ci\u00eancias e Tecnologias Nucleares, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela LRS, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6835-5850","authenticated-orcid":false,"given":"M.","family":"Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica F\u00edsica Rocasolano (IQFR), Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Serrano 119, 28006 Madrid, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,15]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1210\/endo-123-4-1792","article-title":"Identification and characterization of melanotropin binding proteins from M2R melanoma cells by covalent photoaffinity labeling","volume":"123","author":"Gerst","year":"1988","journal-title":"Endocrinology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/S0167-4838(00)00227-2","article-title":"Detection of regions in the MC1 receptor of importance for the selectivity of the MC1 receptor super-selective MS04\/MS05 peptides","volume":"1544","author":"Muceniece","year":"2001","journal-title":"Biochim. 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