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

An improved synthesis of a haptenic heroin surrogate <b>1</b> (6-AmHap) is reported. The intermediate needed for the preparation of <b>1</b> was described in the route in the synthesis of <b>2</b> (DiAmHap). A scalable procedure was developed to install the C-3 amido group. Using the Boc protectng group in <b>18</b> allowed preparation of <b>1</b> in an overall yield of 53% from <b>4</b> and eliminated the necessity of preparing the diamide <b>13</b>. Hapten <b>1</b> was conjugated to tetanus toxoid and mixed with liposomes containing monophosphoryl lipid A as an adjuvant. The <b>1</b> vaccine induced high anti-<b>1</b> 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 <b>1</b> vaccine-induced antibodies bound to heroin and other abused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone, and codeine