{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:18:17Z","timestamp":1788254297522,"version":"build-2803163510"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci?n","doi-asserted-by":"publisher","award":["PID2023-148340OB-I00"],"award-info":[{"award-number":["PID2023-148340OB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Juniper (Juniperus communis L.) berries are widely used as a culinary spice and flavoring ingredient. While their volatile profile is well characterized, much less is known about the composition and biological activity of their nonvolatile constituents. Here, we show that a commercial carbonic extract prepared from juniper berry seasoning displays positive allosteric modulator (PAM)-like activity at the cannabinoid type-1 receptor (CB1R). Bioactivity-guided fractionation identified deoxypodophyllotoxin as a principal contributor to this effect. In the presence of a CB1R orthosteric agonist, this cyclolignan enhanced cAMP- and ERK-dependent signaling and \u03b2-arrestin recruitment, supporting a modulatory interaction with CB1R. Oral administration of the seasoning extract and related cyclolignans altered murine nociceptive responses without impairing motor coordination. These findings identify deoxypodophyllotoxin as a food-derived CB1R modulator and suggest that nonvolatile constituents of juniper berries may contribute to sensory responses associated with food consumption.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c02831","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:02:09Z","timestamp":1786557729000},"page":"26221-26235","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric Modulation\nof the CB1 Receptor by a Juniper\nBerry Seasoning Extract: Deoxypodophyllotoxin as the Major Active\nConstituent"],"prefix":"10.1021","volume":"74","author":[{"given":"Francisco J.","family":"Ponce-Di\u0301az","sequence":"first","affiliation":[{"name":"Instituto Maimo\u0301nides de Investigacio\u0301n Biome\u0301dica de Co\u0301rdoba , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Universidad de Co\u0301rdoba , , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Hospital Universitario Reina Sofi\u0301a , ,","place":["Co\u0301rdoba, Spain, 14004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Cerero-Tejero","sequence":"additional","affiliation":[{"name":"Instituto Maimo\u0301nides de Investigacio\u0301n Biome\u0301dica de Co\u0301rdoba , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Universidad de Co\u0301rdoba , , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Hospital Universitario Reina Sofi\u0301a , ,","place":["Co\u0301rdoba, Spain, 14004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela","family":"Garci\u0301a-Marti\u0301n","sequence":"additional","affiliation":[{"name":"Instituto Maimo\u0301nides de Investigacio\u0301n Biome\u0301dica de Co\u0301rdoba , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Universidad de Co\u0301rdoba , , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Hospital Universitario Reina Sofi\u0301a , ,","place":["Co\u0301rdoba, Spain, 14004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Salamone","sequence":"additional","affiliation":[{"name":"University of Eastern Piedmont , , ,","place":["Novara, Italy, 28100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0949-2799","authenticated-orcid":true,"given":"Federica","family":"Pollastro","sequence":"additional","affiliation":[{"name":"University of Eastern Piedmont , , ,","place":["Novara, Italy, 28100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-9919","authenticated-orcid":true,"given":"Giovanni","family":"Appendino","sequence":"additional","affiliation":[{"name":"University of Eastern Piedmont , , ,","place":["Novara, Italy, 28100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose\u0301 Antonio","family":"Guimare\u0301","sequence":"additional","affiliation":[{"name":"Universidad Complutense de Madrid , , ,","place":["Madrid, Spain, 28040"]},{"name":"Centro de Investigacio\u0301n Biome\u0301dica En Red de Enfermedades Neurodegenerativas (CIBERNED) , ,","place":["Madrid, Spain, 28031"]},{"name":"Instituto Ramo\u0301n y Cajal de Investigacio\u0301n Sanitaria (IRYCIS) , ,","place":["Madrid, Spain, 28034"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u0301a","family":"Go\u0301mez-Can\u0303as","sequence":"additional","affiliation":[{"name":"Universidad Complutense de Madrid , , ,","place":["Madrid, Spain, 28040"]},{"name":"Centro de Investigacio\u0301n Biome\u0301dica En Red de Enfermedades Neurodegenerativas (CIBERNED) , ,","place":["Madrid, Spain, 28031"]},{"name":"Instituto Ramo\u0301n y Cajal de Investigacio\u0301n Sanitaria (IRYCIS) , ,","place":["Madrid, Spain, 28034"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4490-0604","authenticated-orcid":true,"given":"Javier","family":"Ferna\u0301ndez-Ruiz","sequence":"additional","affiliation":[{"name":"Universidad Complutense de Madrid , , ,","place":["Madrid, Spain, 28040"]},{"name":"Centro de Investigacio\u0301n Biome\u0301dica En Red de Enfermedades Neurodegenerativas (CIBERNED) , ,","place":["Madrid, Spain, 28031"]},{"name":"Instituto Ramo\u0301n y Cajal de Investigacio\u0301n Sanitaria (IRYCIS) , ,","place":["Madrid, Spain, 28034"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer de la","family":"Vega","sequence":"additional","affiliation":[{"name":"Universidad de Salamanca, CIETUS, IBSAL , , ,","place":["Salamanca, Spain, 37007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3965-3290","authenticated-orcid":true,"given":"Esther","family":"del Olmo","sequence":"additional","affiliation":[{"name":"Universidad de Salamanca, CIETUS, IBSAL , , ,","place":["Salamanca, Spain, 37007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo San","family":"Feliciano","sequence":"additional","affiliation":[{"name":"Universidad de Salamanca, CIETUS, IBSAL , , ,","place":["Salamanca, Spain, 37007"]},{"name":"Universidade do Vale do Itajai\u0301 (UNIVALI) , , , ,","place":["Itajai\u0301, Santa Catarina, Brazil, 88302-901"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8478-5842","authenticated-orcid":true,"given":"Eduardo","family":"Mun\u0303oz","sequence":"additional","affiliation":[{"name":"Instituto Maimo\u0301nides de Investigacio\u0301n Biome\u0301dica de Co\u0301rdoba , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Universidad de Co\u0301rdoba , , ,","place":["Co\u0301rdoba, Spain, 14004"]},{"name":"Hospital Universitario Reina Sofi\u0301a , ,","place":["Co\u0301rdoba, Spain, 14004"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026090104482737600_cit1","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1002\/9781119114796.ch64","article-title":"Chapter 64: Juniper\nBerry: Juniperus Communis L. (Pinaceae)","volume-title":"Natural Food Flavors and Colorants","author":"Attokaran","year":"2017"},{"issue":"8","key":"2026090104482737600_cit2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2019.e02376","article-title":"Potential\nof Juniperus Communis L as a Nutraceutical in Human\nand Veterinary\nMedicine","volume":"5","author":"Raina","year":"2019","journal-title":"Heliyon"},{"issue":"6","key":"2026090104482737600_cit3","doi-asserted-by":"publisher","first-page":"3197","DOI":"10.3390\/ijms23063197","article-title":"Zimbro (Juniperus\nCommunis L.) as a Promising Source\nof Bioactive Compounds and Biomedical Activities: A Review on Recent\nTrends","volume":"23","author":"Gonc\u0327alves","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"2026090104482737600_cit4","volume-title":"Herbal Medicines. A Guide\nFor Health-Care Professionals","author":"Newall","year":"2002","edition":"2nd"},{"issue":"1","key":"2026090104482737600_cit5","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1021\/ja01097a511","article-title":"Podophyllotoxin from\nJuniperus Species; Savinin","volume":"75","author":"Hartwell","year":"1953","journal-title":"J. Am. Chem. Soc."},{"issue":"15","key":"2026090104482737600_cit6","doi-asserted-by":"publisher","first-page":"8101","DOI":"10.1021\/jf201410p","article-title":"Podophyllotoxin and Deoxypodophyllotoxin\nin Juniperus Bermudiana and 12 Other Juniperus Species: Optimization\nof Extraction, Method Validation, and Quantification","volume":"59","author":"Renouard","year":"2011","journal-title":"J. Agric. Food Chem."},{"issue":"17","key":"2026090104482737600_cit7","doi-asserted-by":"publisher","first-page":"5179","DOI":"10.3390\/molecules26175179","article-title":"Junipers of Various Origins as Potential\nSources of the Anticancer Drug Precursor Podophyllotoxin","volume":"26","author":"Ivanova","year":"2021","journal-title":"Molecules"},{"issue":"1","key":"2026090104482737600_cit8","doi-asserted-by":"publisher","first-page":"79","DOI":"10.2174\/1871520614666140608150448","article-title":"Deoxypodophyllotoxin Isolated from Juniperus Communis\nInduces Apoptosis in Breast Cancer Cells","volume":"15","author":"Benzina","year":"2014","journal-title":"Adv.\nAnticancer Agents Med. 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Neurochem."},{"issue":"17","key":"2026090104482737600_cit11","doi-asserted-by":"publisher","first-page":"5413","DOI":"10.3390\/molecules26175413","article-title":"CB1 Cannabinoid\nReceptor Signaling and Biased Signaling","volume":"26","author":"Leo","year":"2021","journal-title":"Molecules"},{"key":"2026090104482737600_cit12","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3389\/fphar.2018.01259","article-title":"Cannabinoids\nand Pain: New Insights From Old Molecules","volume":"9","author":"Vuc\u030ckovic\u0301","year":"2018","journal-title":"Front.\nPharmacol."},{"key":"2026090104482737600_cit13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3389\/fncel.2016.00294","article-title":"Cannabinoid Receptors\nin the Central Nervous System:\nTheir Signaling and Roles in Disease","volume":"10","author":"Kendall","year":"2017","journal-title":"Front\nCell Neurosci."},{"issue":"1","key":"2026090104482737600_cit14","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrd2760","article-title":"Allosteric Modulators\nof GPCRs: A Novel Approach for the Treatment of CNS Disorders","volume":"8","author":"Jeffrey Conn","year":"2009","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090104482737600_cit15","doi-asserted-by":"publisher","first-page":"110163","DOI":"10.1016\/j.pnpbp.2020.110163","article-title":"CB1 Allosteric\nModulators and Their\nTherapeutic Potential in CNS Disorders","volume":"106","author":"Mielnik","year":"2021","journal-title":"Prog.\nNeuropsychopharmacol Biol. Psychiatry"},{"issue":"13","key":"2026090104482737600_cit16","doi-asserted-by":"publisher","first-page":"2948","DOI":"10.1038\/npp.2015.148","article-title":"A Cannabinoid CB1\nReceptor-Positive Allosteric Modulator\nReduces Neuropathic Pain in the Mouse with No Psychoactive Effects","volume":"40","author":"Ignatowska-Jankowska","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"2026090104482737600_cit17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.pbb.2018.12.009","article-title":"CB1 Positive\nAllosteric Modulation\nAttenuates \u03949-THC Withdrawal and NSAID-Induced Gastric Inflammation","volume":"177","author":"Trexler","year":"2019","journal-title":"Pharmacol., Biochem. Behav."},{"issue":"5","key":"2026090104482737600_cit18","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.tips.2019.03.004","article-title":"Nature-Derived Peptides: A Growing\nNiche for GPCR Ligand Discovery","volume":"40","author":"Muratspahic\u0301","year":"2019","journal-title":"Trends Pharmacol.\nSci."},{"issue":"21","key":"2026090104482737600_cit19","doi-asserted-by":"publisher","first-page":"5060","DOI":"10.3390\/molecules25215060","article-title":"Natural Compounds as Guides for the\nDiscovery of Drugs\nTargeting G-Protein-Coupled Receptors","volume":"25","author":"Serrano-Mari\u0301n","year":"2020","journal-title":"Molecules"},{"key":"2026090104482737600_cit20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/112_2013_11","article-title":"Spices: The\nSavory and Beneficial Science of Pungency","volume":"164","author":"Nilius","year":"2013","journal-title":"Rev.\nPhysiol., Biochem. Pharmacol."},{"issue":"17","key":"2026090104482737600_cit21","doi-asserted-by":"publisher","first-page":"4034","DOI":"10.1111\/bph.15155","article-title":"\u03949 -Tetrahydrocannabinolic Acid Alleviates Collagen-Induced\nArthritis: Role of PPAR\u03b3 and CB1 Receptors","volume":"177","author":"Palomares","year":"2020","journal-title":"Br. J. Pharmacol."},{"issue":"1","key":"2026090104482737600_cit22","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s00394-003-0394-6","article-title":"Non-Pungent Capsaicinoids from Sweet\nPepper Synthesis and Evaluation of the Chemopreventive and Anticancer\nPotential","volume":"42","author":"Macho","year":"2003","journal-title":"Eur. J. Nutr."},{"key":"2026090104482737600_cit23","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.phrs.2016.03.021","article-title":"Biological Characterization\nof PM226, a Chromenoisoxazole, as a Selective CB2 Receptor Agonist\nwith Neuroprotective Profile","volume":"110","author":"Go\u0301mez-Can\u0303as","year":"2016","journal-title":"Pharmacol. Res."},{"issue":"1","key":"2026090104482737600_cit24","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF ChimeraX:\nMeeting\nModern Challenges in Visualization and Analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"issue":"1","key":"2026090104482737600_cit25","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure\nVisualization for Researchers, Educators, and Developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"issue":"11","key":"2026090104482737600_cit26","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX: Tools for Structure\nBuilding and Analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."},{"issue":"3","key":"2026090104482737600_cit27","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1007\/s13311-021-01089-4","article-title":"Betulinic Acid Hydroxamate Is Neuroprotective\nand Induces Protein Phosphatase 2A-Dependent HIF-1\u03b1 Stabilization\nand Post-Transcriptional Dephosphorylation of Prolyl Hydrolase 2","volume":"18","author":"Prados","year":"2021","journal-title":"Neurotherapeutics"},{"issue":"2","key":"2026090104482737600_cit28","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/S0022-3565(25)10668-X","article-title":"Colchicine\nand Cytochalasin B Enhance Cyclic AMP Accumulation via Postreceptor\nActions","volume":"274","author":"Jasper","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"issue":"3","key":"2026090104482737600_cit29","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1083\/jcb.77.3.881","article-title":"Microtubules and Cyclic Amp in Human\nLeukocytes: On the Order of Things","volume":"77","author":"Malawista","year":"1978","journal-title":"J. Cell\nBiol."},{"issue":"1","key":"2026090104482737600_cit30","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/S0026-895X(25)11388-6","article-title":"Inhibitors of Microtubule Assembly Enhance Beta-Adrenergic and Prostaglandin E1-Stimulated Cyclic AMP\nAccumulation in S49 Lymphoma Cells","volume":"16","author":"Kennedy","year":"1979","journal-title":"Mol. Pharmacol."},{"issue":"3","key":"2026090104482737600_cit31","doi-asserted-by":"publisher","first-page":"491","DOI":"10.3934\/biophy.2017.3.491","article-title":"G Protein-Coupled Receptors: The\nEvolution of Structural Insight","volume":"4","author":"Gacasan","year":"2017","journal-title":"AIMS Biophys."},{"issue":"4","key":"2026090104482737600_cit32","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1111\/j.1471-4159.2009.06227.x","article-title":"A Highly Conserved\nTryptophan Residue in the Fourth\nTransmembrane Domain of the A1 Adenosine Receptor Is Essential for\nLigand Binding but Not Receptor Homodimerization","volume":"110","author":"Suzuki","year":"2009","journal-title":"J. Neurochem."}],"container-title":["Journal of Agricultural\nand Food Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jafc.6c02831","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/33\/26221\/66516784\/acs.jafc.6c02831.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jafcau\/article-pdf\/74\/33\/26221\/66516784\/acs.jafc.6c02831.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:48:33Z","timestamp":1788252513000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jafcau\/article\/74\/33\/26221\/5253733\/Allosteric-Modulation-of-the-CB1-Receptor-by-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":32,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,12]]},"published-print":{"date-parts":[[2026,8,26]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jafc.6c02831","relation":{},"ISSN":["0021-8561","1520-5118"],"issn-type":[{"value":"0021-8561","type":"print"},{"value":"1520-5118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]}}}