Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one, <b>1</b>) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of <i>trans</i>-isoquinolinone <b>2</b> (4-aH, 9-<i>O</i>-<i>trans-</i>9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound <b>12</b>. Optical resolution was carried out on <b>2</b>, and each of the enantiomers were used in efficient syntheses of the “unnatural” 4a<i>R</i>,7a<i>S</i>,12b<i>R</i>-(+)-<b>1</b>) and its “natural” enantiomer (−)-<b>1</b>. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (−)-<b>2</b>), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12b<i>R</i>)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo­[2,3]­oxocino­[5,4-<i>c</i>]­pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study

Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one, <b>1</b>) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of <i>trans</i>-isoquinolinone <b>2</b> (4-aH, 9-<i>O</i>-<i>trans-</i>9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound <b>12</b>. Optical resolution was carried out on <b>2</b>, and each of the enantiomers were used in efficient syntheses of the “unnatural” 4a<i>R</i>,7a<i>S</i>,12b<i>R</i>-(+)-<b>1</b>) and its “natural” enantiomer (−)-<b>1</b>. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (−)-<b>2</b>), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12b<i>R</i>)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo­[2,3]­oxocino­[5,4-<i>c</i>]­pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study

Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one, <b>1</b>) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of <i>trans</i>-isoquinolinone <b>2</b> (4-aH, 9-<i>O</i>-<i>trans-</i>9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound <b>12</b>. Optical resolution was carried out on <b>2</b>, and each of the enantiomers were used in efficient syntheses of the “unnatural” 4a<i>R</i>,7a<i>S</i>,12b<i>R</i>-(+)-<b>1</b>) and its “natural” enantiomer (−)-<b>1</b>. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (−)-<b>2</b>), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12b<i>R</i>)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo­[2,3]­oxocino­[5,4-<i>c</i>]­pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study

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

Vaccines against drugs of abuse have induced antibodies in animals that blocked the biological effects of the drug by sequestering the drug in the blood and preventing it from crossing the blood-brain barrier. Drugs of abuse are too small to induce antibodies and, therefore, require conjugation of drug hapten analogs to a carrier protein. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant. Previously, we have shown that <b>1</b> (MorHap), a heroin/morphine hapten, conjugated to tetanus toxoid (TT) and mixed with liposomes containing monophosphoryl lipid A [L­(MPLA)] as adjuvant, partially blocked the antinociceptive effects of heroin in mice. Herein, we extended those findings, demonstrating greatly improved vaccine induced antinociceptive effects up to 3% mean maximal potential effect (%MPE). This was obtained by evaluating the effects of vaccine efficacy of hapten <b>1</b> vaccine conjugates with varying hapten densities using two different commonly used carrier proteins, TT and cross-reactive material 197 (CRM₁₉₇). Immunization of mice with these conjugates mixed with L­(MPLA) induced very high anti-<b>1</b> IgG peak levels of 400–1500 μg/mL that bound to both heroin and its metabolites, 6-acetylmorphine and morphine. Except for the lowest hapten density for each carrier, the antibody titers and affinity were independent of hapten density. The TT carrier based vaccines induced long-lived inhibition of heroin-induced antinociception that correlated with increasing hapten density. The best formulation contained TT with the highest hapten density of ≥30 haptens/TT molecule and induced %MPE of approximately 3% after heroin challenge. In contrast, the best formulation using CRM₁₉₇ was with intermediate <b>1</b> densities (10–15 haptens/CRM₁₉₇ molecule), but the %MPE was approximately 13%. In addition, the chemical synthesis of <b>1</b>, the optimization of the conjugation method, and the methods for the accurate quantification of hapten density are described

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