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The Alkaloids. Chemistry and Biology 2021This chapter provides a short overview of the history of morphine since it's isolation by Sertürner in 1805. The biosynthesis of the title alkaloid as well as all total... (Review)
Review
This chapter provides a short overview of the history of morphine since it's isolation by Sertürner in 1805. The biosynthesis of the title alkaloid as well as all total and formal syntheses of morphine and codeine published after 1996 are discussed in detail. The last section of this chapter provides a detailed overview of medicinally relevant derivatives of the title alkaloid.
Topics: Alkaloids; Biology; Codeine; Morphine
PubMed: 34565506
DOI: 10.1016/bs.alkal.2021.04.001 -
Current Drug Research Reviews 2021Naltrexone (NTX) is an opioid antagonist that inhibits cell proliferation in vivo when administered in low doses. Naltrexone in low doses can reduce tumor growth by... (Review)
Review
Naltrexone (NTX) is an opioid antagonist that inhibits cell proliferation in vivo when administered in low doses. Naltrexone in low doses can reduce tumor growth by interfering with cell signalling as well as by modifying the immune system. It acts as an Opioid Growth Factor receptor (OGFr) antagonist and the OGF-OGFr axis is an inhibitory biological pathway present in human cancer cells and tissues, being a target for the treatment with naltrexone low-dose (LDN). Clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors. LDN shows promising results for people with primary cancer of the bladder, breast, liver, lung, lymph nodes, colon and rectum. This short review provides further evidence to support the role of LDN as an anticancer agent.
Topics: Antineoplastic Agents; Cell Proliferation; Humans; Naltrexone; Narcotic Antagonists; Neoplasms
PubMed: 33504322
DOI: 10.2174/2589977513666210127094222 -
Nature Jan 2023Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side...
Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site found in µOR and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp residue in the Na site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G, G and G subtypes and arrestins, thus modulating their in vivo pharmacology.
Topics: Animals; Mice; Analgesics, Opioid; Arrestins; Cryoelectron Microscopy; Fentanyl; Ligands; Morphinans; Receptors, Opioid, mu; Binding Sites; Nociception; Drug Design
PubMed: 36450356
DOI: 10.1038/s41586-022-05588-y -
American Journal of Obstetrics &... Jan 2021
Topics: Buprenorphine; Methadone
PubMed: 33451602
DOI: 10.1016/j.ajogmf.2020.100236 -
Chemical Record (New York, N.Y.) Sep 2021The morphinans are an important class of structurally fascinating and physiologically important natural products as exemplified by the famous opium alkaloids of the... (Review)
Review
The morphinans are an important class of structurally fascinating and physiologically important natural products as exemplified by the famous opium alkaloids of the morphine family. Although this class of secondary metabolites from the juice of the opium poppy capsule was already used for medicinal purposes thousands of years ago, chemical modifications are still being applied to the core structure today in order to achieve the most specific effect on the various receptor subtypes possible with the fewest possible side effects. The unusual architecture of the morphinan core has also proven to be a highly challenging target for total synthesis. This review highlights electrosynthetic approaches towards natural and semisynthetic morphinan alkaloids. The historical progress in applying anodic aryl-aryl couplings to the construction of the morphinan framework is described in chronological order while particular benefits and challenges concerning the electrochemical transformations are grouped together, including the influence of substitution patterns, protecting groups, and reaction conditions.
Topics: Morphinans; Morphine; Papaver
PubMed: 33955153
DOI: 10.1002/tcr.202100078 -
Canadian Family Physician Medecin de... Dec 2020
Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Dose-Response Relationship, Drug; Humans; Naloxone; Opioid-Related Disorders; Substance Withdrawal Syndrome
PubMed: 33334955
DOI: 10.46747/cfp.6612891 -
CJEM Oct 2023
Topics: Humans; Buprenorphine, Naloxone Drug Combination; Buprenorphine; Emergency Service, Hospital; Analgesics, Opioid
PubMed: 37805957
DOI: 10.1007/s43678-023-00594-z -
Molecules (Basel, Switzerland) Jun 2023Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of... (Review)
Review
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to -methylmorphinans to limit their ability to cross the blood-brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.
Topics: Humans; Analgesics, Opioid; Morphinans; Pain; Analgesics; Morphine; Receptors, Opioid, mu
PubMed: 37375318
DOI: 10.3390/molecules28124761 -
The Alkaloids. Chemistry and Biology 2023Morphinan alkaloids have attracted constant attention since the isolation of morphine by Sertürner in 1805. However, a group of 45 compounds possessing a complete...
Morphinan alkaloids have attracted constant attention since the isolation of morphine by Sertürner in 1805. However, a group of 45 compounds possessing a complete ent-morphinan backbone can also be found in the literature. These compounds are related to the morphinandienone subgroup and display a substitution pattern which is different from the morphinans. In particular, these alkaloids could be substituted at position C-2 and C-8 either by a hydroxy function or a methoxy moiety. Four groups of ent-morphinan alkaloids can be proposed, the salutaridine, pallidine, cephasugine and erromangine series. Interestingly, the botanical distribution of the ent-morphinans is more widespread than for the morphinans and includes the Annonaceae, Berberidaceae, Euphorbiaceae, Fumariaceae, Hernandiaceae, Lauraceae, Menispermaceae, Monimiaceae, Papaveraceae, and Ranunculaceae families. To date, their exact mode of production remains elusive and their interplay with the biosynthetic pathway of other classes of benzyltetrahydroisoquinoline alkaloids, in particular aporphines, should be confirmed. Exploration of the biological and therapeutic potential of these compounds is limited to some areas, namely central nervous system (CNS), inflammation, cancer, malaria and viruses. Further studies should be conducted to identify the cellular/molecular targets in view of promoting these compounds as new scaffolds in medicinal chemistry.
Topics: Humans; Morphinans; Morphine; Annonaceae; Aporphines; Biology
PubMed: 37716795
DOI: 10.1016/bs.alkal.2023.07.001 -
Mayo Clinic Proceedings Oct 2019The United States is in the midst of a national opioid epidemic. Physicians are encouraged both to prevent and treat opioid-use disorders (OUDs). Although there are 3... (Review)
Review
The United States is in the midst of a national opioid epidemic. Physicians are encouraged both to prevent and treat opioid-use disorders (OUDs). Although there are 3 Food and Drug Administration-approved medications to treat OUD (methadone, buprenorphine, and naltrexone) and there is ample evidence of their efficacy, they are not used as often as they should. We provide a brief review of the 3 primary medications used in the treatment of OUD. Using data from available medical literature, we synthesize existing knowledge and provide a framework for how to determine the optimal approach for outpatient management of OUD with medication-assisted treatments.
Topics: Algorithms; Buprenorphine; Decision Trees; Humans; Methadone; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 31543255
DOI: 10.1016/j.mayocp.2019.03.029