{
  "abstract": "Stabilizing β-turn geometry through macrocyclization has been a key determinant of receptor selectivity and functional activity in melanocortin peptide ligands. In addition to conformational constraint, macrocycle size plays a critical role in modulating receptor recognition. In this study, we report a novel library of downsized MT-II and SHU-9119 analogues featuring 20- and 19-membered macrocycles, generated through lactam and thioether cyclization strategies while preserving the canonical His–dPhe/dNal(2)–Arg–Trp pharmacophore. Functional evaluation revealed that these reduced macrocycles retained activity at the human melanocortin-3 and -4 receptors (hMC3R and hMC4R), with key structural elements governing receptor preference and agonist versus antagonist behavior within this receptor subset. Three new hMC4R agonists were identified: the lactam-linked peptides 6 and 10 and the thioether-linked peptide 14. In addition, the thioether-linked peptide 15 exhibited weak partial agonist activity and functional antagonism at hMC4R. Notably, peptide 14 showed subnanomolar hMC4R agonist potency (pEC50 = 9.55) and 84-fold functional preference for hMC4R over hMC3R. These findings identify the 20-membered thioether-containing architecture as particularly favourable for achieving potent hMC4R agonism and enhanced functional preference over hMC3R.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacy, University of Naples Federico II Naples 80131 Italy",
    "Life Sciences Institute, University of Michigan Ann Arbor MI 48109 USA",
    "Department of Molecular and Integrative Physiology, University of Michigan Ann Arbor MI 48109 USA",
    "Department of Molecular, Cellular, and Developmental Biology, University of Michigan Ann Arbor MI 48109 USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rosa Bellavita",
      "orcid": "0000-0003-2163-5163"
    },
    {
      "affs": [
        1
      ],
      "name": "Luis E. Gimenez",
      "orcid": "0000-0002-0110-2135"
    },
    {
      "affs": [
        1
      ],
      "name": "Savannah Y. Williams",
      "orcid": "0000-0003-3083-894X"
    },
    {
      "affs": [
        0
      ],
      "name": "Ida Boccino",
      "orcid": "0009-0002-6662-007X"
    },
    {
      "affs": [
        0
      ],
      "name": "Gennaro M. Bailo",
      "orcid": "0009-0007-4843-6283"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Roger D. Cone",
      "orcid": "0000-0003-3333-5651"
    },
    {
      "affs": [
        0
      ],
      "name": "Paolo Grieco",
      "orcid": "0000-0002-6854-8123"
    },
    {
      "affs": [
        0
      ],
      "name": "Francesco Merlino",
      "orcid": "0000-0002-9607-229X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8qe7qj8kktj5f.bib",
  "cited_by": 0,
  "doi": "10.1039/d6md00726k",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736795/",
  "id": "8qe7qj8kktj5f",
  "issns": [
    "2632-8682"
  ],
  "landing_url": "https://doi.org/10.1039/d6md00726k",
  "language": "en",
  "licence": "CC-BY-3.0",
  "licence_label": "CC BY 3.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/3.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Chemistry"
    ],
    [
      "openalex",
      "1605|Chemical Synthesis and Analysis"
    ]
  ],
  "openalex": "W7223094308",
  "pdf_url": null,
  "pmcid": "PMC13736795",
  "pmid": "42991890",
  "published": "2026-10-21",
  "publisher": "Royal Society of Chemistry",
  "ris": "https://research.draconitic.com/paper/8qe7qj8kktj5f.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:10Z",
      "native_id": "PMC13736795",
      "source": "pmc",
      "url": "https://doi.org/10.1039/d6md00726k"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Chemical Synthesis and Analysis",
      "subfield": "organic"
    }
  ],
  "title": "Downsizing macrocycles in melanocortin peptide analogues: thioether and lactam cyclization strategies to modulate hMC3/4R agonism and antagonism",
  "title_text": "Downsizing macrocycles in melanocortin peptide analogues: thioether and lactam cyclization strategies to modulate hMC3/4R agonism and antagonism",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:10Z",
  "url": "https://research.draconitic.com/paper/8qe7qj8kktj5f",
  "venue": "RSC Medicinal Chemistry",
  "versions": []
}