{
  "abstract": "Allosteric modulation of G protein-coupled receptors (GPCR) is a rapidly advancing area of drug discovery with considerable therapeutic potential. In this study, we used various bioluminescence resonance energy transfer (BRET) assay configurations to investigate the differential activity of LY3154207, a dopamine D1 receptor (D1R)- positive allosteric modulator (PAM), in potentiating D1R-mediated signaling pathways. Our data showed that LY3154207 demonstrated clear bias toward {beta}-arrestin recruitment over G-protein engagement. Among the G-protein subtypes, LY3154207 preferentially potentiated Gs signaling induced by DA. Interestingly, when tested for its effect on the Gs-selective D1R agonist DHX and the Golf-selective agonist TAV, LY3154207 further enhanced the selectivity of these compounds, suggesting a probe-dependent effect. We also studied the structural mechanism underlying this subtype selectivity and found that W123 and R130 in the intracellular loop 2 (ICL2) of D1R were crucial for the activity of LY3154207. Furthermore, the N domain of the G-protein appeared to make minor contributions to this G-protein subtype selectivity of LY3154207. Lastly, our data demonstrated that LY3154207 induced cAMP production in the absence of the orthosteric ligand, indicating that this compound is an ago-PAM.",
  "abstract_shown": true,
  "affiliations": [
    "Northeastern University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "A. M. Nguyen"
    },
    {
      "name": "H. Umaoka"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Yano"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5dw7gsh2afw2q.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.26.754724",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754724v1.full",
  "id": "5dw7gsh2afw2q",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754724v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7216030237",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754724v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5dw7gsh2afw2q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:45Z",
      "native_id": "10.64898/2026.09.26.754724",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754724v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "DIFFERENTIAL ACTIVATION OF G-PROTEIN SUBTYPES BY DOPAMINE D1 RECEPTOR ALLOSTERIC MODULATION",
  "title_text": "DIFFERENTIAL ACTIVATION OF G-PROTEIN SUBTYPES BY DOPAMINE D1 RECEPTOR ALLOSTERIC MODULATION",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:45Z",
  "url": "https://research.draconitic.com/paper/5dw7gsh2afw2q",
  "venue": "bioRxiv",
  "versions": []
}