ChemInform Abstract: STEREOSPECIFIC SYNTHESIS OF THE 6BETA‐HYDROXY METABOLITES OF NALTREXONE AND NALOXONE

Chatterjie, Nithiananda; Inturrisi, C. E.; Dayton, Hyman B.; Blumberg, Harold

doi:10.1002/chin.197535392

Cited by 3 publications

(7 citation statements)

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“…It is possible that pharmacological actions of 6-alpha-and 6-beta-naloxol differ from naloxone in other respects. For example, there is some evidence that 6-alpha-naloxol is a weak agonist (Chatterjie and Inturrisi, 1975). Such activity might result in less CPA following morphine pretreatment by substituting for morphine and alleviating morphine withdrawal.…”

Section: Discussionmentioning

confidence: 99%

“…Such activity might result in less CPA following morphine pretreatment by substituting for morphine and alleviating morphine withdrawal. However, 6-beta-naloxol was reported to have no such partial agonist activity (Chatterjie and Inturrisi, 1975) and naloxone itself has been reported to be a weak agonist (Fukuda et al, 1998;Liu and Prather, 2001;Wang et al, 2004) making such an explanation unlikely. Since the receptor binding profiles of 6-alphaand 6-beta-naloxol are incomplete, it is possible that these drugs interact, differentially from naloxone, with other, non-mu opioid, receptor systems resulting in counteraction of the morphine enhancement of both CPA and withdrawal jumping.…”

Section: Discussionmentioning

confidence: 99%

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Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Shoblock

Maidment

2005

Neuropsychopharmacol

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Naloxone administration produces a robust conditioned place aversion (CPA) in opiate-naive rodents by blocking the action of enkephalins at mu opioid receptors. This aversive response is potentiated by prior exposure to morphine. In vitro studies indicate that morphine treatment may promote constitutive activity of mu opioid receptors. We hypothesized that such enhanced constitutive activity in vivo may underlie the increased aversive property of naloxone by uncovering the inverse agonist property of this drug. The CPA produced by naloxone was compared with that produced by the neutral antagonists 6-alpha-and 6-beta-naloxol in mice with and without prior morphine exposure. While all three drugs produced CPA, only naloxone CPA was enhanced by morphine given 20 h prior to each naloxone injection. Furthermore, only naloxone produced withdrawal jumping when given 20 h after morphine, even though 6-alpha-naloxol was able to produce jumping when given 4 h after morphine. These data suggest that morphine may enhance naloxone CPA by increasing levels of constitutively active mu receptors and further support the role of such constitutive activity in mediating naloxone-precipitated physical withdrawal. Such long-term changes in constitutive activity of the mu receptor induced by exogenous opiate exposure may thus be an important factor in hedonic homeostatic dysregulation proposed to underlie the addictive process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Shoblock

Maidment

2005

Neuropsychopharmacol

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“…The tricyclic ring system of the antidepressant drug amitriptyline has inspired many endeavors toward molecular modifications.1'2 During an SAR study of tetracyclic analogues, an attempt was made to synthesize 7Hbenzo [5,6]cycloocta[l,2,3-de]naphthalen-7-one (l). 3 We report an intramolecular Friedel-Crafts acylation of 3benzyl-l/f,3H-naphtho[l, 8-cd]pyran-l-one (2) in polyphosphoric acid (PPA).…”

mentioning

confidence: 99%

Intramolecular Friedel-Crafts acylation of a lactone in polyphosphoric acid. Synthesis of 2-phenylphenalen-1-one

Asscher¹,

Agranat²

1980

J. Org. Chem.

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“…ΔGmmgbsa values determined using the MMGBSA method showed that the binding affinity was energetically more favorable for NTX than for its derivatives, explaining the higher potency of NTX compared with NTXOL, which is also a MOR antagonist but a hundred times less potent than NTX [32]. However, despite NTXOL showing a lower affinity, many other factors contribute to its lower potency, such as entropic effects, which we didn't explore with the MMGBSA approach.…”

Section: Discussionmentioning

confidence: 97%

“…The major metabolite of NTX in humans and other animal species is 6-β-naltrexol (NTXOL), and 2-hydroxy-3-O-methylnaltrexol (HMNTXOL) is another minor metabolite. NTXOL is also an opioid receptor agonist but is hundreds of times less potent than NTX at the mu-receptor [32]. Molecular modeling analysis based on molecular mechanics and semi-empirical calculations has shown that NTXOL and NTX share a comparable surface area and volume, indicating that both substrates may have a similar affinity for the same binding site in opioid receptors [33].…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis of Inhibitory Mechanism of Naltrexone and Its Metabolites through Structural and Energetic Analyses

Bello¹

2022

Preprint

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Naltrexone (NTX) is a potent opioid antagonist with good blood-brain barrier permeability, targeting different endogenous opioid receptors, particularly the mu-opioid receptor (MOR). Therefore, it represents a promising candidate for drug development against drug addiction. However, the details of the molecular interactions of NTX and its derivatives with MOR are not fully understood, hindering ligand-based drug discovery. In the present study, taking advantage of the high-resolution X-ray crystal structure of the murine MOR (mMOR), we constructed a homology model of the human MOR (hMOR). A solvated phospholipid bilayer was built around the hMOR and submitted to microsecond (µs) molecular dynamics (MD) simulations to obtain an optimized hMOR model. NTX and its derivatives were docked into the optimized hMOR model and submitted to µs MD simulations in an aqueous membrane system. The MD simulation results were submitted to Molecular Mechanics Generalized-Born surface area (MMGBSA) binding free energy calculations and principal component analysis. Our results revealed that NTX and its derivatives showed differences in protein-ligand interactions; however, they shared contact with residues at TM2, TM3, H6, and TM7. The binding free energy and principal component analysis revealed the structural and energetic effects responsible for the higher potency of NTX compared to its derivatives.

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ChemInform Abstract: STEREOSPECIFIC SYNTHESIS OF THE 6BETA‐HYDROXY METABOLITES OF NALTREXONE AND NALOXONE

Abstract: Naltrexon (Ia) und Naloxon (IIa) werden mit Formamidin‐sulfinsäure zu (Ib) bzw. (IIb) reduziert.

Cited by 3 publications

References 1 publication

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Intramolecular Friedel-Crafts acylation of a lactone in polyphosphoric acid. Synthesis of 2-phenylphenalen-1-one

Molecular Basis of Inhibitory Mechanism of Naltrexone and Its Metabolites through Structural and Energetic Analyses

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