{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T11:11:41Z","timestamp":1770894701150,"version":"3.50.1"},"reference-count":44,"publisher":"Elsevier BV","issue":"3","license":[{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["jpet.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"published-print":{"date-parts":[[2024,6]]},"DOI":"10.1124\/jpet.123.001735","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T20:40:16Z","timestamp":1713213616000},"page":"301-309","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a Novel \u03b4 Opioid Receptor-Selective Agonist Chemotype"],"prefix":"10.1016","volume":"389","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5801-1608","authenticated-orcid":false,"given":"Yazan J.","family":"Meqbil","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jhoan","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arryn T.","family":"Blaine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Cassell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amynah A.","family":"Pradhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"van Rijn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1124\/jpet.123.001735_bib1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2022.914651","article-title":"Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions","volume":"13","author":"Blaine","year":"2022","journal-title":"Front Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib2","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuropharm.2023.109526","article-title":"Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures","volume":"232","author":"Blaine","year":"2023","journal-title":"Neuropharmacology"},{"key":"10.1124\/jpet.123.001735_bib3","doi-asserted-by":"crossref","first-page":"17057","DOI":"10.1021\/jacs.9b08085","article-title":"Selection of DNA-encoded libraries to protein targets within and on living cells","volume":"141","author":"Cai","year":"2019","journal-title":"J Am Chem Soc"},{"key":"10.1124\/jpet.123.001735_bib4","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/s41589-023-01292-8","article-title":"A community biased signaling atlas","volume":"19","author":"Caroli","year":"2023","journal-title":"Nat Chem Biol"},{"key":"10.1124\/jpet.123.001735_bib5","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.euroneuro.2018.12.013","article-title":"Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides","volume":"29","author":"Cassell","year":"2019","journal-title":"Eur Neuropsychopharmacol"},{"key":"10.1124\/jpet.123.001735_bib6","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1021\/acschemneuro.5b00208","article-title":"Novel synthesis and pharmacological characterization of NOP receptor agonist 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198)","volume":"6","author":"Chang","year":"2015","journal-title":"ACS Chem Neurosci"},{"key":"10.1124\/jpet.123.001735_bib7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J Neurosci Methods"},{"key":"10.1124\/jpet.123.001735_bib8","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/bph.13374","article-title":"\u03b2-Arrestin 2 dependence of \u03b4 opioid receptor agonists is correlated with alcohol intake","volume":"173","author":"Chiang","year":"2016","journal-title":"Br J Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib9","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.aax9115","article-title":"Elucidating the active \u03b4-opioid receptor crystal structure with peptide and small-molecule agonists","volume":"5","author":"Claff","year":"2019","journal-title":"Sci Adv"},{"key":"10.1124\/jpet.123.001735_bib10","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1124\/jpet.119.258640","article-title":"A novel G protein-biased agonist at the \u03b4 opioid receptor with analgesic efficacy in models of chronic pain","volume":"372","author":"Conibear","year":"2020","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1124\/jpet.123.001735_bib11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature12944","article-title":"Molecular control of \u03b4-opioid receptor signalling","volume":"506","author":"Fenalti","year":"2014","journal-title":"Nature"},{"key":"10.1124\/jpet.123.001735_bib12","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nsmb.2965","article-title":"Structural basis for bifunctional peptide recognition at human \u03b4-opioid receptor","volume":"22","author":"Fenalti","year":"2015","journal-title":"Nat Struct Mol Biol"},{"key":"10.1124\/jpet.123.001735_bib13","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J Med Chem"},{"key":"10.1124\/jpet.123.001735_bib14","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J Med Chem"},{"key":"10.1124\/jpet.123.001735_bib15","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2021.764885","article-title":"Evaluation of kratom opioid derivatives as potential treatment option for alcohol use disorder","volume":"12","author":"Gutridge","year":"2021","journal-title":"Front Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib16","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1111\/bph.14913","article-title":"G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder","volume":"177","author":"Gutridge","year":"2020","journal-title":"Br J Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib17","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1124\/mi.6.3.7","article-title":"The antidepressant -like effects of delta-opioid receptor agonists","volume":"6","author":"Jutkiewicz","year":"2006","journal-title":"Mol Interv"},{"key":"10.1124\/jpet.123.001735_bib18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1021\/cn200111m","article-title":"A simple method for quantifying functional selectivity and agonist bias","volume":"3","author":"Kenakin","year":"2012","journal-title":"ACS Chem Neurosci"},{"key":"10.1124\/jpet.123.001735_bib19","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1111\/bph.15811","article-title":"Community guidelines for GPCR ligand bias: IUPHAR review 32","volume":"179","author":"Kolb","year":"2022","journal-title":"Br J Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv Drug Deliv Rev"},{"key":"10.1124\/jpet.123.001735_bib21","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: improving force field accuracy on challenging regimes of chemical space","volume":"17","author":"Lu","year":"2021","journal-title":"J Chem Theory Comput"},{"key":"10.1124\/jpet.123.001735_bib22","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/s41586-019-0917-9","article-title":"Ultra-large library docking for discovering new chemotypes","volume":"566","author":"Lyu","year":"2019","journal-title":"Nature"},{"key":"10.1124\/jpet.123.001735_bib23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nature19112","article-title":"Structure-based discovery of opioid analgesics with reduced side effects","volume":"537","author":"Manglik","year":"2016","journal-title":"Nature"},{"key":"10.1124\/jpet.123.001735_bib24","doi-asserted-by":"crossref","first-page":"7236","DOI":"10.3390\/molecules26237236","article-title":"Identification of a novel delta opioid receptor agonist chemotype with potential negative allosteric modulator capabilities","volume":"26","author":"Meqbil","year":"2021","journal-title":"Molecules"},{"key":"10.1124\/jpet.123.001735_bib25","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3390\/ph15070873","article-title":"Opportunities and challenges for in silico drug discovery at delta opioid receptors","volume":"15","author":"Meqbil","year":"2022","journal-title":"Pharmaceuticals (Basel)"},{"key":"10.1124\/jpet.123.001735_bib26","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tips.2011.06.008","article-title":"The delta opioid receptor: an evolving target for the treatment of brain disorders","volume":"32","author":"Pradhan","year":"2011","journal-title":"Trends Pharmacol Sci"},{"key":"10.1124\/jpet.123.001735_bib27","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1523\/JNEUROSCI.4124-15.2016","article-title":"Agonist-specific recruitment of arrestin isoforms differentially modify delta opioid receptor function","volume":"36","author":"Pradhan","year":"2016","journal-title":"J Neurosci"},{"key":"10.1124\/jpet.123.001735_bib28","doi-asserted-by":"crossref","first-page":"16459","DOI":"10.1523\/JNEUROSCI.3748-10.2010","article-title":"Ligand-directed trafficking of the \u03b4-opioid receptor in vivo: two paths toward analgesic tolerance","volume":"30","author":"Pradhan","year":"2010","journal-title":"J Neurosci"},{"key":"10.1124\/jpet.123.001735_bib29","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41589-022-01208-y","article-title":"Insights into distinct signaling profiles of the \u00b5OR activated by diverse agonists","volume":"19","author":"Qu","year":"2023","journal-title":"Nat Chem Biol"},{"key":"10.1124\/jpet.123.001735_bib30","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1007\/s00213-015-4195-4","article-title":"A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression","volume":"233","author":"Richards","year":"2016","journal-title":"Psychopharmacology (Berl)"},{"key":"10.1124\/jpet.123.001735_bib31A","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fpsyt.2018.00112","article-title":"Critical Role for Gi\/o-Protein Activity in the Dorsal Striatum in the Reduction of Voluntary Alcohol Intake in C57Bl\/6 Mice","volume":"9","author":"Robins","year":"2018","journal-title":"Front Psychiatry"},{"key":"10.1124\/jpet.123.001735_bib31","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1021\/acschembio.5b00712","article-title":"Proposed mode of binding and action of positive allosteric modulators at opioid receptors","volume":"11","author":"Shang","year":"2016","journal-title":"ACS Chem Biol"},{"key":"10.1124\/jpet.123.001735_bib32","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1039\/D1MD00025J","article-title":"Modulating \u03b2-arrestin 2 recruitment at the \u03b4- and \u03bc-opioid receptors using peptidomimetic ligands","volume":"12","author":"Sharma","year":"2021","journal-title":"RSC Med Chem"},{"key":"10.1124\/jpet.123.001735_bib33","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1002\/jcc.20267","article-title":"A fast, scalable method for the parallel evaluation of distance-limited pairwise particle interactions","volume":"26","author":"Shaw","year":"2005","journal-title":"J Comput Chem"},{"key":"10.1124\/jpet.123.001735_bib34","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","article-title":"Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules","volume":"21","author":"Shelley","year":"2007","journal-title":"J Comput Aided Mol Des"},{"key":"10.1124\/jpet.123.001735_bib35","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41586-020-2027-0","article-title":"Virtual discovery of melatonin receptor ligands to modulate circadian rhythms","volume":"579","author":"Stein","year":"2020","journal-title":"Nature"},{"key":"10.1124\/jpet.123.001735_bib36","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/sj.bjp.0703661","article-title":"(8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4. 5]dec-3-yl)-acetic acid methyl ester (NNC 63-0532) is a novel potent nociceptin receptor agonist","volume":"131","author":"Thomsen","year":"2000","journal-title":"Br J Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib37","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1124\/mol.113.088880","article-title":"Quantification of ligand bias for clinically relevant \u03b22-adrenergic receptor ligands: implications for drug taxonomy","volume":"85","author":"van der Westhuizen","year":"2014","journal-title":"Mol Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00213-013-3129-2","article-title":"Pharmacological traits of delta opioid receptors: pitfalls or opportunities?","volume":"228","author":"van Rijn","year":"2013","journal-title":"Psychopharmacology (Berl)"},{"key":"10.1124\/jpet.123.001735_bib39A","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1111\/bph.14353","article-title":"Tolerance to high-internalizing \u03b4 opioid receptor agonist is critically mediated by arrestin 2","volume":"175","author":"Vicente-Sanchez","year":"2018","journal-title":"Br J Pharmacol"},{"key":"10.1124\/jpet.123.001735_bib39","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.neuroscience.2016.06.028","article-title":"The delta opioid receptor tool box","volume":"338","author":"Vicente-Sanchez","year":"2016","journal-title":"Neuroscience"},{"key":"10.1124\/jpet.123.001735_bib40","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/cn100008c","article-title":"Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties","volume":"1","author":"Wager","year":"2010","journal-title":"ACS Chem Neurosci"},{"key":"10.1124\/jpet.123.001735_bib41","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1016\/S0960-894X(99)00385-6","article-title":"8-Acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists","volume":"9","author":"Wichmann","year":"1999","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1124\/jpet.123.001735_bib42","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/acs.biochem.0c00658","article-title":"Predicted mode of binding to and allosteric modulation of the \u03bc-opioid receptor by kratom\u2019s alkaloids with reported antinociception in vivo","volume":"60","author":"Zhou","year":"2021","journal-title":"Biochemistry"}],"container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524172576?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356524172576?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1124\/jpet.123.001735","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T15:19:08Z","timestamp":1739978348000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022356524172576"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6]]},"references-count":44,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,6]]}},"alternative-id":["S0022356524172576"],"URL":"https:\/\/doi.org\/10.1124\/jpet.123.001735","relation":{},"ISSN":["0022-3565"],"issn-type":[{"value":"0022-3565","type":"print"}],"subject":[],"published":{"date-parts":[[2024,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a Novel \u03b4 Opioid Receptor-Selective Agonist Chemotype","name":"articletitle","label":"Article Title"},{"value":"The Journal of Pharmacology and Experimental Therapeutics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1124\/jpet.123.001735","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 by The American Society for Pharmacology and Experimental Therapeutics","name":"copyright","label":"Copyright"}]}}