6 research outputs found
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