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

Configurational Reassignment and Improved Preparation of the Competitive IL-6 Receptor Antagonist 20<i>R</i>,21<i>R</i>-Epoxyresibufogenin-3-formate

20<i>R</i>,21<i>R</i>-Epoxyresibufogenin-3-formate (<b>1</b>) and 20<i>S</i>,21<i>S</i>-epoxyresibufogenin-3-formate (<b>2</b>) were synthesized from commercial resibufogenin (<b>3</b>) using known procedures. The major product (<b>1</b>) was dextrorotatory, as was the major product from the reported synthesis of epoxyresibufogenin-3-formate; however, the literature (+)-compound was assigned the 20<i>S</i>,21<i>S</i>-configuration on the basis of NMR data. We have now unequivocally determined, using single-crystal X-ray structure analyses of the major and minor products of the synthesis and of their derivatives, that the major product from the synthesis was (+)-20<i>R</i>,21<i>R</i>-epoxyresibufogenin-3-formate (<b>1</b>). Our minor synthetic product was determined to have the (−)-20<i>S</i>,21<i>S</i>-configuration (<b>2</b>). The (+)-20<i>R</i>,21<i>R</i>-compound <b>1</b> has been found to have high affinity for the IL-6 receptor and to act as an IL-6 antagonist. A greatly improved synthesis of <b>1</b> was achieved through oxidation of preformed resibufogenin-3-formate. This has enabled us to prepare, from the very expensive commercial resibufogenin, considerably larger quantities of <b>1</b>, the only known nonpeptide small-molecule IL-6 antagonist

Clinically Employed Opioid Analgesics Produce Antinociception via μ‑δ Opioid Receptor Heteromers in Rhesus Monkeys

Morphine and related drugs are widely employed as analgesics despite the side effects associated with their use. Although morphine is thought to mediate analgesia through mu opioid receptors, delta opioid receptors have been implicated in mediating some side effects such as tolerance and dependence. Here we present evidence in rhesus monkeys that morphine, fentanyl, and possibly methadone selectively activate mu-delta heteromers to produce antinociception that is potently antagonized by the delta opioid receptor antagonist, naltrindole (NTI). Studies with HEK293 cells expressing mu-delta heteromeric opioid receptors exhibit a similar antagonism profile of receptor activation in the presence of NTI. In mice, morphine was potently inhibited by naltrindole when administered intrathecally, but not intracerebroventricularly, suggesting the possible involvement of mu-delta heteromers in the spinal cord of rodents. Taken together, these results strongly suggest that, in primates, mu-delta heteromers are allosterically coupled and mediate the antinociceptive effects of three clinically employed opioid analgesics that have been traditionally viewed as mu-selective. Given the known involvement of delta receptors in morphine tolerance and dependence, our results implicate mu-delta heteromers in mediating both antinociception and these side effects in primates. These results open the door for further investigation in humans

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