{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T13:31:24Z","timestamp":1775914284899,"version":"3.50.1"},"reference-count":99,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["TKP 2021 EGA-25"],"award-info":[{"award-number":["TKP 2021 EGA-25"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated as haptens to a carrier protein will elicit the production of antibodies capable of reacting specifically with the unconjugated hapten or its parent compound. The position of the attachment in opioid haptens to the carrier protein will influence the specificity of the antiserum produced in immunized animals with the hapten\u2013carrier conjugate. Immunoassays for the determination of opioid drugs are based on the ability of drugs to inhibit the reaction between drug-specific antibodies and the corresponding drug\u2013carrier conjugate or the corresponding labelled hapten. Pharmacological studies of the hapten\u2013carrier conjugates resulted in the development of vaccines for treating opioid use disorders (OUDs). Immunotherapy for opioid addiction includes the induction of anti-drug vaccines which are composed of a hapten, a carrier protein, and adjuvants. In this review we survey the design of opioid haptens, the development of the opioid radioimmunoassay, and the results of immunotherapy for OUDs.<\/jats:p>","DOI":"10.3390\/ijms25147781","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T15:05:51Z","timestamp":1721142351000},"page":"7781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Opioid-Based Haptens: Development of Immunotherapy"],"prefix":"10.3390","volume":"25","author":[{"given":"S\u00e1ndor","family":"Hosztafi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9., H-1092 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Rita","family":"Galambos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1-rad t\u00e9r 4., H-1445 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1678-233X","authenticated-orcid":false,"given":"Istv\u00e1n","family":"K\u00f6teles","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9., H-1092 Budapest, Hungary"},{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D\u00e1vid \u00c1","family":"Kar\u00e1di","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1-rad t\u00e9r 4., H-1445 Budapest, Hungary"},{"name":"Department of Anesthesiology and Intensive Therapy, Semmelweis University, \u00dcll\u0151i \u00fat 78., H-1082 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"F\u00fcrst","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1-rad t\u00e9r 4., H-1445 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8488-3266","authenticated-orcid":false,"given":"Mahmoud","family":"Al-Khrasani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1-rad t\u00e9r 4., H-1445 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"ref_1","first-page":"103","article-title":"The Immunological Assay of Drugs","volume":"29","author":"Butler","year":"1977","journal-title":"Pharmacol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/252708a0","article-title":"Changes in Heroin Self-Administration by a Rhesus Monkey after Morphine Immunisation","volume":"252","author":"Bonese","year":"1974","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1124\/jpet.111.189506","article-title":"An Oxycodone Conjugate Vaccine Elicits Drug-Specific Antibodies That Reduce Oxycodone Distribution to Brain and Hot-Plate Analgesia","volume":"341","author":"Pravetoni","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJMra1507771","article-title":"Opioid Abuse in Chronic Pain\u2014Misconceptions and Mitigation Strategies","volume":"374","author":"Volkow","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_5","first-page":"535","article-title":"Cancer Pain and Opioid Use Disorder","volume":"36","author":"Ganguly","year":"2022","journal-title":"Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/nyas.14209","article-title":"Epidemiology of the U.S. Opioid Crisis: The Importance of the Vector","volume":"1451","author":"Compton","year":"2019","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0140-6736(21)02252-2","article-title":"Responding to the Opioid Crisis in North America and beyond: Recommendations of the Stanford\u2013Lancet Commission","volume":"399","author":"Humphreys","year":"2022","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.forsciint.2015.10.021","article-title":"Postmortem Tissue Distribution of Acetyl Fentanyl, Fentanyl and Their Respective nor-Metabolites Analyzed by Ultrahigh Performance Liquid Chromatography with Tandem Mass Spectrometry","volume":"257","author":"Poklis","year":"2015","journal-title":"Forensic Sci. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1056\/NEJMc1204141","article-title":"Effect of Abuse-Deterrent Formulation of OxyContin","volume":"367","author":"Cicero","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.drugpo.2017.06.005","article-title":"Naloxone for Heroin, Prescription Opioid, and Illicitly Made Fentanyl Overdoses: Challenges and Innovations Responding to a Dynamic Epidemic","volume":"46","author":"Fairbairn","year":"2017","journal-title":"Int. J. Drug Policy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1146\/annurev-publhealth-031914-122957","article-title":"The Prescription Opioid and Heroin Crisis: A Public Health Approach to an Epidemic of Addiction","volume":"36","author":"Kolodny","year":"2015","journal-title":"Annu. Rev. Public Health"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/j.1749-6632.2011.06199.x","article-title":"Designer Drugs: A Medicinal Chemistry Perspective","volume":"1248","author":"Carroll","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.drugpo.2015.04.003","article-title":"Fentanyls: Are We Missing the Signs? Highly Potent and on the Rise in Europe","volume":"26","author":"Mounteney","year":"2015","journal-title":"Int. J. Drug Policy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1177\/00027162221149285","article-title":"The Opioid Crisis, Health, Healthcare, and Crime: A Review of Quasi-Experimental Economic Studies","volume":"703","author":"Maclean","year":"2022","journal-title":"Ann. Am. Acad. Political Soc. Sci."},{"key":"ref_15","first-page":"1347","article-title":"Morphine: Radioimmunoassay","volume":"168","author":"Spector","year":"1970","journal-title":"Science (1979)"},{"key":"ref_16","first-page":"253","article-title":"Quantitative Determination of Morphine in Serum by Radioimmunoassay","volume":"178","author":"Spector","year":"1971","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","first-page":"281","article-title":"Antibodies to Morphine, Barbiturates, and Serotonin","volume":"25","author":"Spector","year":"1973","journal-title":"Pharmacol. Rev."},{"key":"ref_18","first-page":"1143","article-title":"Morphine-3-Succinyl-Bovine Serum Albumin: An Immunogenic Hapten-Protein Conjugate","volume":"176","author":"Wainer","year":"1972","journal-title":"Science (1979)"},{"key":"ref_19","first-page":"647","article-title":"The Structure of Morphine Monohemisuccinate","volume":"178","author":"Wainer","year":"1972","journal-title":"Science (1979)"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0014-2999(76)90211-9","article-title":"Radioimmunoassay for the Simultaneous Determination of Morphine and Codeine","volume":"38","author":"Gintzler","year":"1976","journal-title":"Eur. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1093\/clinchem\/21.10.1498","article-title":"Iodination of Morphine and Dihydromorphine, as Related to Radioimmunoassay","volume":"21","author":"Davis","year":"1975","journal-title":"Clin. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1002\/jlcr.2580181015","article-title":"Preparation of 2-iodomorphine for Use in Radioimmunoassay","volume":"18","author":"Mason","year":"1981","journal-title":"J. Label. Comp. Radiopharm."},{"key":"ref_23","first-page":"514","article-title":"Vunakis Specificities of Antibodies to Morphine","volume":"180","author":"Wasserman","year":"1972","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0024-3205(77)90138-2","article-title":"2-Diazomorphine Directed Antiserum: Determination of Morphine in Brain after Naloxone Challenge in Morphine Pellet Implanted Mice","volume":"20","author":"Catlin","year":"1977","journal-title":"Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0161-5890(74)90133-3","article-title":"Critical Antigenic Determinants for Production of Antibody to Distinguish Morphine from Heroin, Codeine and Dextromethorphan","volume":"11","author":"Cross","year":"1974","journal-title":"Mol. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0031-6989(76)90022-9","article-title":"Comparison of Immunogenicity of Opiates Bound to Protein at Different Sites on the Molecule: N-Carboxy Morphine-BSA","volume":"8","author":"Herndon","year":"1976","journal-title":"Pharmacol. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0021-5198(19)32118-3","article-title":"Antibodies to Bsa Conjugates of Morphine Derivatives: Strict Dependency of the Immunological Specificity on the Hapten Structure","volume":"24","author":"Koida","year":"1974","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1254\/jjp.24.707","article-title":"The Morphine 3-Glucuronide Directed Antibody: Its Immunological Specificity and Possible Use for Radioimmunoassay of Morphine in Urine","volume":"24","author":"Koida","year":"1974","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/0024-3205(76)90043-6","article-title":"A Codeine Radioimmunoassay Exhibiting Insignificant Cross-Reactivity with Morphine. (Preliminary Communication)","volume":"19","author":"Findlay","year":"1976","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0022-1759(93)90080-Q","article-title":"Characterization of Morphine-Specific Monoclonal Antibodies Showing Minimal Cross-Reactivity with Codeine","volume":"157","author":"Usagawa","year":"1993","journal-title":"J. Immunol. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3109\/15563658008989987","article-title":"RIA Opiates: Structure versus Reactivity","volume":"17","author":"Budd","year":"1980","journal-title":"Clin. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/clinchem\/19.2.216","article-title":"A Sensitive, Rapid Radioimmunoassay for Morphine and Immunologically Related Substances in Urine and Serum","volume":"19","author":"Catlin","year":"1973","journal-title":"Clin. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/clinchem\/20.2.243","article-title":"Evaluation of Immunoassay Methods for Detection, in Urine, of Drugs Subject to Abuse","volume":"20","author":"Bastos","year":"1974","journal-title":"Clin. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/clinchem\/21.1.81","article-title":"Radioimmunoassay of Drugs Subject to Abuse: Critical Evaluation of Urinary Morphine Barbiturate, Morphine, Barbiturate, and Amphetamine Assays","volume":"21","author":"Mule","year":"1975","journal-title":"Clin. Chem."},{"key":"ref_35","first-page":"527","article-title":"The Influence of Physiologic and Pharmacologic Factors on the Disposition of Morphine as Determined by Radioimmunoassay","volume":"191","author":"Berkowitz","year":"1975","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","first-page":"224","article-title":"Pharmacokinetics of Morphine by Radioimmunoassay: The Influence of Immunochemical Factors","volume":"200","author":"Catlin","year":"1977","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/jps.2600720107","article-title":"Morphine Radioimmunoassay Specificity before and after Extraction of Plasma and Cerebrospinal Fluid","volume":"72","author":"Grabinski","year":"1983","journal-title":"J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/jps.2600710313","article-title":"Morphine Pharmacokinetics: GLC Assay versus Radioimmunoassay","volume":"71","author":"Stanski","year":"1982","journal-title":"J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1177\/000456328402100415","article-title":"Sensitive and Specific Morphine Radioimmunoassay with Iodine Label: Pharmacokinetics of Morphine in Man after Intravenous Administration","volume":"21","author":"Moore","year":"1984","journal-title":"Ann. Clin. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1177\/000456328702400205","article-title":"Analysis of Morphine and Its Major Metabolites by Differential Radioimmunoassay","volume":"24","author":"Hand","year":"1987","journal-title":"Ann. Clin. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S0140-6736(85)91519-3","article-title":"Morphine-6-Glucuronide, an Important Factor in Interpreting Morphine Radioimmunoassays","volume":"326","author":"Aherne","year":"1985","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/j.1365-2125.1989.tb05399.x","article-title":"The Bioavailability and Pharmacokinetics of Morphine after Intravenous, Oral and Buccal Administration in Healthy Volunteers","volume":"27","author":"Hoskin","year":"1989","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0731-7085(94)90011-6","article-title":"Evaluation of a Differential Radioimmunoassay Technique for the Determination of Morphine and Morphine-6-Glucuronide in Human Plasma","volume":"12","author":"Chapman","year":"1994","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8661","DOI":"10.1016\/0040-4039(95)01786-H","article-title":"Synthesis of a Morphine-6-Glucuronide Hapten, N-(4-Aminobutyl)Normorphine-6-Glucuronide, and Related Haptens","volume":"36","author":"Brown","year":"1995","journal-title":"Tetrahedron Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1177\/000456329503200306","article-title":"A Specific Radioimmunoassay for the Determination of Morphine-6-Glucuronide in Human Plasma","volume":"32","author":"Chapman","year":"1995","journal-title":"Ann. Clin. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s004140050190","article-title":"A Specific Immunoassay for the Determination of Morphine and Its Glucuronides in Human Blood","volume":"112","author":"Beike","year":"1998","journal-title":"Int. J. Leg. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"173718","DOI":"10.1016\/j.ejphar.2020.173718","article-title":"Effect of the Morphine\/Heroin Vaccine on Opioid and Non-Opioid Drug-Induced Antinociception in Mice","volume":"891","author":"Miramontes","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3232","DOI":"10.1016\/j.vaccine.2006.01.047","article-title":"A Novel Bivalent Morphine\/Heroin Vaccine That Prevents Relapse to Heroin Addiction in Rodents","volume":"24","author":"Anton","year":"2006","journal-title":"Vaccine"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"214","DOI":"10.4161\/hv.5.4.7556","article-title":"Vaccines against Morphine\/Heroin and Its Use as Effective Medication for Preventing Relapse to Opiate Addictive Behaviors","volume":"5","author":"Anton","year":"2009","journal-title":"Hum. Vaccin."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1111\/j.1471-4159.2011.07502.x","article-title":"A Morphine\/Heroin Vaccine with New Hapten Design Attenuates Behavioral Effects in Rats","volume":"119","author":"Li","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1093\/clinchem\/27.9.1524","article-title":"Relationships between Immunogen Structure and Antisera Specificity in the Narcotic Alkaloid Series","volume":"27","author":"Findlay","year":"1981","journal-title":"Clin. Chem."},{"key":"ref_52","first-page":"1290","article-title":"Evidence for Active Immunity to Morphine in Mice","volume":"178","author":"Berkowitz","year":"1972","journal-title":"Science (1979)"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/0024-3205(74)90016-2","article-title":"Influence of Active and Passive Immunity on the Disposition of Dihydromorphine-H3","volume":"15","author":"Berkowitz","year":"1974","journal-title":"Life Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/241537a0","article-title":"In Vitro Morphine Antagonism by Antibodies","volume":"241","author":"Wainer","year":"1973","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/0091-3057(78)90295-2","article-title":"Effects of Passive Immunization against Morphine on Heroin Self-Administration","volume":"9","author":"Killian","year":"1978","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1080\/21645515.2021.1935171","article-title":"Synergistic Immune and Antinociceptive Effects Induced from the Combination of Two Different Vaccines against Morphine\/Heroin in Mouse","volume":"17","year":"2021","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1124\/pr.117.013904","article-title":"Conjugate Vaccine Immunotherapy for Substance Use Disorder","volume":"69","author":"Bremer","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/clpt.2011.281","article-title":"Vaccines against Drug Abuse","volume":"91","author":"Shen","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.tips.2018.08.001","article-title":"Immunopharmacotherapies for Treating Opioid Use Disorder","volume":"39","author":"Banks","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5","DOI":"10.15252\/embr.201745322","article-title":"Vaccines to Combat the Opioid Crisis","volume":"19","author":"Olson","year":"2018","journal-title":"EMBO Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"107662","DOI":"10.1016\/j.neuropharm.2019.06.001","article-title":"Development of Vaccines to Treat Opioid Use Disorders and Reduce Incidence of Overdose","volume":"158","author":"Pravetoni","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.drudis.2019.07.009","article-title":"Immunotherapy for Treating Methamphetamine, Heroin and Cocaine Use Disorders","volume":"25","author":"Xiaoshan","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5195","DOI":"10.1021\/jm200461m","article-title":"A Vaccine Strategy That Induces Protective Immunity against Heroin","volume":"54","author":"Stowe","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_64","first-page":"865","article-title":"Developing a Vaccine Against Multiple Psychoactive Targets: A Case Study of Heroin","volume":"10","author":"Schlosburg","year":"2012","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9036","DOI":"10.1073\/pnas.1219159110","article-title":"Dynamic Vaccine Blocks Relapse to Compulsive Intake of Heroin","volume":"110","author":"Schlosburg","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"10776","DOI":"10.1021\/jm301262z","article-title":"Investigating the Effects of a Hydrolytically Stable Hapten and a Th1 Adjuvant on Heroin Vaccine Performance","volume":"55","author":"Bremer","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8601","DOI":"10.1021\/jacs.7b03334","article-title":"Development of a Clinically Viable Heroin Vaccine","volume":"139","author":"Bremer","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Belz, T.F., Bremer, P.T., Zhou, B., Blake, S., Ellis, B., Eubanks, L.M., and Janda, K.D. (2020). Sulfonate-Isosteric Replacement Examined within Heroin-Hapten Vaccine Design. Bioorg. Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127388"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"153045","DOI":"10.1016\/j.tetlet.2021.153045","article-title":"Vaccine Design through Transition State Mimicry of Heroin Hydrolysis","volume":"71","author":"Belz","year":"2021","journal-title":"Tetrahedron Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1021\/jacs.8b09756","article-title":"Chemical Interventions for the Opioid Crisis: Key Advances and Remaining Challenges","volume":"141","author":"Olson","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"13294","DOI":"10.1021\/jacs.0c05219","article-title":"Enhancement of a Heroin Vaccine through Hapten Deuteration","volume":"142","author":"Belz","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1016\/j.vaccine.2013.04.027","article-title":"Liposomes Containing Monophosphoryl Lipid A: A Potent Adjuvant System for Inducing Antibodies to Heroin Hapten Analogs","volume":"31","author":"Matyas","year":"2013","journal-title":"Vaccine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7211","DOI":"10.1039\/C4OB01053A","article-title":"Synthesis and Immunological Effects of Heroin Vaccines","volume":"12","author":"Li","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5927","DOI":"10.1007\/s00216-014-8035-x","article-title":"Characterization and Optimization of Heroin Hapten-BSA Conjugates: Method Development for the Synthesis of Reproducible Hapten-Based Vaccines","volume":"406","author":"Torres","year":"2014","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1007\/s00216-015-9223-z","article-title":"A Simple Nonradioactive Method for the Determination of the Binding Affinities of Antibodies Induced by Hapten Bioconjugates for Drugs of Abuse","volume":"408","author":"Torres","year":"2016","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.vaccine.2014.01.028","article-title":"Facial Recognition of Heroin Vaccine Opiates: Type 1 Cross-Reactivities of Antibodies Induced by Hydrolytically Stable Haptenic Surrogates of Heroin, 6-Acetylmorphine, and Morphine","volume":"32","author":"Matyas","year":"2014","journal-title":"Vaccine"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1021\/acs.bioconjchem.5b00085","article-title":"Efficacy, but Not Antibody Titer or Affinity, of a Heroin Hapten Conjugate Vaccine Correlates with Increasing Hapten Densities on Tetanus Toxoid, but Not on CRM197 Carriers","volume":"26","author":"Jalah","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1021\/acs.jmedchem.7b01427","article-title":"A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross-React Immunologically with Related Drugs of Abuse","volume":"61","author":"Sulima","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1039\/D1CB00029B","article-title":"Synthesis and Immunological Effects of C14-Linked 4,5-Epoxymorphinan Analogues as Novel Heroin Vaccine Haptens","volume":"2","author":"Gutman","year":"2021","journal-title":"RSC Chem. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Sulima, A., Li, F., Morgan, J.B., Truong, P., Antoline, J.F.G., Oertel, T., Barrientos, R.C., Torres, O.B., Beck, Z., and Imler, G.H. (2022). Design, Synthesis, and In Vivo Evaluation of C1-Linked 4,5-Epoxymorphinan Haptens for Heroin Vaccines. Molecules, 27.","DOI":"10.3390\/molecules27051553"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1016\/j.vaccine.2012.04.101","article-title":"Co-Administration of Morphine and Oxycodone Vaccines Reduces the Distribution of 6-Monoacetylmorphine and Oxycodone to Brain in Rats","volume":"30","author":"Pravetoni","year":"2012","journal-title":"Vaccine"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1021\/jm3013745","article-title":"Reduced Antinociception of Opioids in Rats and Mice by Vaccination with Immunogens Containing Oxycodone and Hydrocodone Haptens","volume":"56","author":"Pravetoni","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1520\/JFS13045J","article-title":"Fentanyl-Related Deaths: Demographics, Circumstances, and Toxicology of 112 Cases","volume":"36","author":"Henderson","year":"1991","journal-title":"J. Forensic Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/S0196-0644(05)81216-8","article-title":"China White Epidemic: An Eastern United States Emergency Department Experience","volume":"20","author":"Martin","year":"1991","journal-title":"Ann. Emerg. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/ADM.0000000000000324","article-title":"Misuse of Novel Synthetic Opioids: A Deadly New Trend","volume":"11","author":"Prekupec","year":"2017","journal-title":"J. Addict. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3772","DOI":"10.1002\/anie.201511654","article-title":"Combatting Synthetic Designer Opioids: A Conjugate Vaccine Ablates Lethal Doses of Fentanyl Class Drugs","volume":"55","author":"Bremer","year":"2016","journal-title":"Angew. Chem.-Int. Ed."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1021\/acschemneuro.8b00079","article-title":"Efficacious Vaccine against Heroin Contaminated with Fentanyl","volume":"9","author":"Hwang","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.3762\/bjoc.15.100","article-title":"A Chemically Contiguous Hapten Approach for a Heroin-Fentanyl Vaccine","volume":"15","author":"Natori","year":"2019","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Park, H., Lee, J.C., Eubanks, L.M., Ellis, B., Zhou, B., and Janda, K.D. (2021). Improvements on a Chemically Contiguous Hapten for a Vaccine to Address Fentanyl-Contaminated Heroin. Bioorg. Med. Chem., 41.","DOI":"10.1016\/j.bmc.2021.116225"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1021\/acschemneuro.0c00064","article-title":"Evaluation of a Dual Fentanyl\/Heroin Vaccine on the Antinociceptive and Reinforcing Effects of a Fentanyl\/Heroin Mixture in Male and Female Rats","volume":"11","author":"Townsend","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1021\/acs.molpharmaceut.0c00837","article-title":"Developing Translational Vaccines against Heroin and Fentanyl through Investigation of Adjuvants and Stability","volume":"18","author":"Blake","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1124\/jpet.118.253674","article-title":"A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats","volume":"368","author":"Raleigh","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"14647","DOI":"10.1021\/acs.jmedchem.0c01042","article-title":"Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity","volume":"63","author":"Robinson","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1124\/jpet.112.201194","article-title":"Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats","volume":"344","author":"Raleigh","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1124\/jpet.117.247049","article-title":"Opioid Dose-And Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats","volume":"365","author":"Raleigh","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41541-023-00697-9","article-title":"A TLR7\/8 Agonist Increases Efficacy of Anti-Fentanyl Vaccines in Rodent and Porcine Models","volume":"8","author":"Crouse","year":"2023","journal-title":"NPJ Vaccines"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"K\u00f6teles, I., Maz\u00e1k, K., T\u00f3th, G., T\u0171z, B., and Hosztafi, S. (2020). Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants. Molecules, 25.","DOI":"10.3390\/molecules25174009"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"K\u00f6teles, I., Maz\u00e1k, K., T\u00f3th, G., Horv\u00e1th, P., Kiss, E., T\u0171z, B., and Hosztafi, S. (2021). Synthesis of 3-O-Carboxyalkyl Morphine Derivatives and Characterization of Their Acid-Base Properties. Chem. Biodivers., 18.","DOI":"10.1002\/cbdv.202100135"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Z\u00e1dor, F., Mohammadzadeh, A., Balogh, M., Z\u00e1dori, Z.S., Kir\u00e1ly, K., Barsi, S., Galambos, A.R., L\u00e1szl\u00f3, S.B., Hutka, B., and V\u00e1radi, A. (2020). Comparisons of in Vivo and in Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-Sulfate and Codeine-6-O-Sulfate. Molecules, 25.","DOI":"10.3390\/molecules25061370"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7781\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:17:44Z","timestamp":1760109464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7781"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,16]]},"references-count":99,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147781"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147781","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,16]]}}}