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.

Autor: Sulima A; Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services , 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States., Jalah R; U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine , 6720A Rockledge Drive, Bethesda, Maryland 20817, United States.; U.S. Military HIV Research Program, Walter Reed Army Institute of Research , 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Antoline JFG; Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services , 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States., Torres OB; U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine , 6720A Rockledge Drive, Bethesda, Maryland 20817, United States.; U.S. Military HIV Research Program, Walter Reed Army Institute of Research , 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Imler GH; Center for Biomolecular Science and Engineering, Naval Research Laboratory , Washington D.C. 20375, United States., Deschamps JR; Center for Biomolecular Science and Engineering, Naval Research Laboratory , Washington D.C. 20375, United States., Beck Z; U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine , 6720A Rockledge Drive, Bethesda, Maryland 20817, United States.; U.S. Military HIV Research Program, Walter Reed Army Institute of Research , 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Alving CR; U.S. Military HIV Research Program, Walter Reed Army Institute of Research , 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Jacobson AE; Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services , 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States., Rice KC; Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services , 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States., Matyas GR; U.S. Military HIV Research Program, Walter Reed Army Institute of Research , 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2018 Jan 11; Vol. 61 (1), pp. 329-343. Date of Electronic Publication: 2017 Dec 29.
DOI: 10.1021/acs.jmedchem.7b01427
Abstrakt: An improved synthesis of a haptenic heroin surrogate 1 (6-AmHap) is reported. The intermediate needed for the preparation of 1 was described in the route in the synthesis of 2 (DiAmHap). A scalable procedure was developed to install the C-3 amido group. Using the Boc protectng group in 18 allowed preparation of 1 in an overall yield of 53% from 4 and eliminated the necessity of preparing the diamide 13. Hapten 1 was conjugated to tetanus toxoid and mixed with liposomes containing monophosphoryl lipid A as an adjuvant. The 1 vaccine induced high anti-1 IgG levels that reduced heroin-induced antinociception and locomotive behavioral changes following repeated subcutaneous and intravenous heroin challenges in mice and rats. Vaccinated mice had reduced heroin-induced hyperlocomotion following a 50 mg/kg heroin challenge. The 1 vaccine-induced antibodies bound to heroin and other abused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone, and codeine.
Databáze: MEDLINE
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