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

Abstract

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.

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

“…Maximum antinociceptive potency shifts following vaccine administration were approximately 3-and 5-fold for IV and SC heroin, respectively and lasted for at least seven-toeight weeks. The present results are consistent with previous heroin conjugate vaccine studies in male and female mice (Bremer et al, 2017;Bremer et al, 2014;Hwang et al, 2018a;Hwang et al, 2018b;Hwang et al, 2018c;Jalah et al, 2015;Matyas et al, 2014;Sulima et al, 2017) and Schwienteck 15 male rats (Schlosburg et al, 2013;Stowe et al, 2011;Sulima et al, 2017). The present results extended these previous findings to the inclusion of female rats and no sex difference in vaccine effectiveness was observed.…”

“…SC and IV) in male and female rats. A warmwater tail withdrawal procedure is one preclinical behavioral procedure to efficiently assess vaccine effectiveness over time and selectivity (Schlosburg et al, 2013;Stowe et al, 2011;Sulima et al, 2017). In addition, the present study also assessed heroin vaccine selectivity for the heroin metabolites 6-AM and morphine and the structurally dissimilar MOR (mu-opioid receptor) ligand fentanyl.…”

Heat shock proteins: A dual carrier-adjuvant for an anti-drug vaccine against heroin

“…There have been some notable advances in the development of vaccines against heroin 1, 5-6 and other drugs of abuse. 7-10 These vaccines have been shown to stimulate the immune system to produce antibodies that bind drug molecules in systemic circulation.…”

Alum adjuvant is more effective than MF59 at prompting early germinal center formation in response to peptide-protein conjugates and enhancing efficacy of a vaccine against opioid use disorders

“…The preclinical efficacy of vaccines against heroin and prescription opioids depends upon generating opioid-specific antibodies that selectively reduce opioid distribution to the brain, opioidinduced behavior, and toxicity associated with fatal overdoses in mice, rats and non-human primates. [2][3][4][5][6][7][8][9] In immunized rats, greater vaccine efficacy correlated with higher individual opioid-specific serum IgG antibody titers. 2,10 In immunized mice, vaccine efficacy correlated with the frequency of naïve and early activated hapten-specific B cells and carrier-specific T cells, as well as the formation of germinal centers (GC) in secondary lymphoid organsan essential component of the adaptive immune response to vaccines.…”