{
  "abstract": "Small-molecule agonists of class B1 G-protein-coupled receptors (GPCRs) remain rare because these receptors typically require large extracellular peptide ligands for activation. PCO371 is a notable exception: an intracellular non-peptide agonist, originally developed for osteoporosis treatment, that activates parathyroid hormone 1 receptor (PTH1R) from the cytoplasmic face of the receptor and is considered Gs-protein biased. In this study, we compared the functional, pharmacological and structural properties of PCO371 with the canonical extracellular peptide agonist PTH 1-34 at the PTH1R to define the molecular mechanisms underlying PCO371's unusual signalling profile. By manipulating receptor reserve, we demonstrate that PCO371 is a partial agonist relative to PTH 1-34, contrary to previous observations. Across Gs, Gi3, Gq, cAMP, and {beta}-arrestin-2 pathways, operational model analysis showed that PCO371 is non-biased, engaging the same transducers as PTH1-34 but with ~1000-fold lower potency. Mechanistic modelling using the Cubic Ternary Complex Activation model revealed that reduced intrinsic efficacy is sufficient to reproduce PCO371's distinct monotonic signalling kinetics, providing a quantitative explanation for its partial agonism. PCO371 binding is {beta}-arrestin-compatible but only drives measurable {beta}-arrestin-2 recruitment when PTH1R is highly expressed. Molecular modelling suggests that PC0371 stable binding needs an intact receptor-G protein complex. Overall, these insights define the mechanistic basis of intracellular agonism at a class B1 GPCR and provide a framework for designing next-generation small-molecule modulators that exploit this emerging pharmacological space.",
  "abstract_shown": true,
  "affiliations": [
    "Coventry University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "F. Napier Khwaja"
    },
    {
      "name": "Z. Mariam"
    },
    {
      "name": "Y. Abdolhay"
    },
    {
      "name": "T. Redfern-Nichols"
    },
    {
      "name": "G. Ladds"
    },
    {
      "name": "D. Poyner"
    },
    {
      "name": "G. Deganutti"
    },
    {
      "name": "M. Wheatley"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Ayub"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aeth9rdx4208c.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.05.27.728112",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.05.27.728112v2.full",
  "id": "aeth9rdx4208c",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.05.27.728112v2",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.05.27.728112v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-05-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/aeth9rdx4208c.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:37Z",
      "native_id": "10.64898/2026.05.27.728112",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.05.27.728112v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "PCO371 intracellular agonism at the parathyroid hormone 1 receptor produces pan-activation of signalling partners",
  "title_text": "PCO371 intracellular agonism at the parathyroid hormone 1 receptor produces pan-activation of signalling partners",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:37Z",
  "url": "https://research.draconitic.com/paper/aeth9rdx4208c",
  "venue": "bioRxiv",
  "versions": []
}