{"entity": "researcher", "timestamp": "2026-10-01T13:13:31.455Z", "family": "Dahl\u00e9n", "given": "Johan", "initials": "J", "orcid": "0000-0002-6804-1517", "affiliations": ["Department of Physics, Chemistry and Biology, Link\u00f6ping University, SE 581 85 Link\u00f6ping, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/377687a14be14663bf7114588f3b628a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/377687a14be14663bf7114588f3b628a"}}, "publications": [{"entity": "publication", "iuid": "b1b1f019469f452f91497c2b5de421a8", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b1b1f019469f452f91497c2b5de421a8.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b1b1f019469f452f91497c2b5de421a8"}}, "title": "Structure-activity relationship of prevalent synthetic cannabinoid metabolites on hCB1 in vitro and in silico dynamics.", "authors": [{"family": "\u00c5strand", "given": "Anna", "initials": "A", "orcid": "0000-0001-7486-7537", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1fba87bf8d3f48eaa5affaac68e1f0f6.json"}}, {"family": "Laudadio", "given": "Emiliano", "initials": "E", "orcid": "0000-0002-8053-6539", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7bb431d4c98948b3b88db6bb496626bc.json"}}, {"family": "Gameli", "given": "Prince S", "initials": "PS", "orcid": "0009-0001-3194-3250", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3055aabd3d194eefac3bf0ec68db3e41.json"}}, {"family": "Martin", "given": "Laura", "initials": "L"}, {"family": "Carlier", "given": "Jeremy", "initials": "J", "orcid": "0000-0003-3332-9518", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/25758c4fba4a4d829fca85a25e9ca980.json"}}, {"family": "Busard\u00f2", "given": "Francesco P", "initials": "FP", "orcid": "0000-0002-3082-4532", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7edcb847b27e454bb746ae4ae0903be8.json"}}, {"family": "Dahl\u00e9n", "given": "Johan", "initials": "J", "orcid": "0000-0002-6804-1517", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/377687a14be14663bf7114588f3b628a.json"}}, {"family": "Wu", "given": "Xiongyu", "initials": "X", "orcid": "0000-0001-6756-2276", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/740b03ae6734491c98c8d6ceec78563b.json"}}, {"family": "Konradsson", "given": "Peter", "initials": "P", "orcid": "0000-0002-3416-0139", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fd5c89de502f41968f6974d3c573fd61.json"}}, {"family": "Vikingsson", "given": "Svante", "initials": "S", "orcid": "0000-0001-5977-3049", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/13dc8d93d33545dc8d1191e84c3d0831.json"}}, {"family": "Kronstrand", "given": "Robert", "initials": "R", "orcid": "0000-0002-4222-9597", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3d098651dd2141e2bc1ac9b21573c0c6.json"}}, {"family": "Gr\u00e9en", "given": "Henrik", "initials": "H", "orcid": "0000-0002-8015-5728", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/26cbd40a5c7d41f0976e6f4c8c1d2e21.json"}}], "type": "journal article", "published": "2026-03-00", "journal": {"title": "Acta Pharmacol Sin", "issn": "1745-7254", "volume": "47", "issue": "3", "pages": "776-789", "issn-l": null}, "abstract": "Synthetic cannabinoids (SC) target the human cannabinoid receptor 1 (hCB1) and are extensively metabolized, but the metabolite activity on the hCB1 receptor after a SC intake is largely unknown. In this study we compared the in vitro hCB1 receptor activity of 26 metabolites of the synthetic cannabinoid receptor agonists (SCRA) JWH-018, AM-2201, THJ-018 and THJ-2201 as a model system for SC metabolite activity to elucidate their structure-activity relationships. The efficacy and potency of metabolites were assessed using an AequoScreen hCB1 receptor assay in triplicates and 7-8 concentration points (20 \u00b5g/mL-9.5 ng/mL) were used to construct dose-response curves and to determine EC50 and Emax. In silico docking and molecular dynamics were performed using a model of the active form of the hCB1 receptor with all the metabolites. Final poses were simulated to assess stability under physiological conditions. We showed that carboxylic acid metabolites and 2-hydroxyindole biotransformational products were inactive, while 5-hydroxypentyl SCRA metabolites decreased efficacy to <70%, qualifying them as partial agonists. Eighteen metabolites retained >70% efficacy of their parent compound. Metabolite potencies ranged from 13-3500 nM where the most potent were the 4-hydroxypentyl derivatives of THJ-2201 and THJ-018 and the 4-hydroxyindole derivatives of AM-2201 and JWH-018, also known to be prevalent in vivo metabolites. The efficacy data from in silico experiments were correlated with the in vitro results demonstrating a linear trend (R2 = 0.9457), significant (P < 0.0001) at the 95% confident interval between the binding energies and efficacies of the compounds investigated. In silico analysis with docking and molecular dynamics simulations showed that active metabolites maintained a minimum of six amino acid interactions involving all substructures. The in silico molecular dynamics simulations revealed that the efficacy and potency seemed to be driven by a complex network of hydrophobic weak amino acid-ligand interactions. Most prevalent were CH-\u03c0 interactions and \u03c0-\u03c0 stackings. This study demonstrates the clear structure-activity relationships well correlated to the molecular dynamics simulations, suggesting that metabolites, especially the 4-hydroxy pentyl metabolites, may contribute to the overall effect of SCs in vivo.", "doi": "10.1038/s41401-025-01678-5", "pmid": "41184621", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12932713"}, {"db": "pii", "key": "10.1038/s41401-025-01678-5"}], "notes": [], "created": "2026-10-01T08:28:49.621Z", "modified": "2026-10-01T08:28:50.077Z"}]}