ArticleDrug metabolism and disposition: the biological fate of chemicals2011
Preclinical disposition (in vitro) of novel μ-opioid receptor selective antagonists.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- How Subtle Molecular Differences in the Morphinan Opioid Antagonists Affect Their Physicochemical and In Vitro ADME Properties.ACS medicinal chemistry letters · 2026Article
- Blocking potential metabolic sites on NAT to improve its safety profile while retaining the pharmacological profile.Bioorganic chemistry · 2024Article
- Preclinical Characterization and Development on NAQ as a Mu Opioid Receptor Partial Agonist for Opioid Use Disorder Treatment.ACS pharmacology & translational science · 2022Article
- Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists.Journal of medicinal chemistry · 2022Article
- Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment.Journal of medicinal chemistry · 2022Article
- Developmental Considerations for the Use of Naltrexone in Children and Adolescents.The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2021Article
- Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators.Journal of computer-aided molecular design · 2020Article
- Pharmacological characterization of 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[(3'-fluoro-4'-pyridyl)acetamido]morphinan (NFP) as a dual selective MOR/KOR ligand with potential applications in treating opioid use disorder.European journal of pharmacology · 2019Article
- Characterization of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN) as a Novel Opioid Receptor Modulator for Opioid Use Disorder Treatment.ACS chemical neuroscience · 2019Article
- Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands.Journal of medicinal chemistry · 2019Article
- Methylation Products of 6β- N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators.ACS chemical neuroscience · 2018Article
- In vitro and in vivo functional profile characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ) as a low efficacy mu opioid receptor modulator.European journal of pharmacology · 2018Article
- Synthesis and evaluation of a ligand targeting the μ and δ opioid receptors for drug delivery to lung cancer.Bioorganic & medicinal chemistry letters · 2017Article
- Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator To Treat Opioid-Induced Constipation.ACS medicinal chemistry letters · 2017Article
- Synthesis and pharmacological evaluation of novel selective MOR agonist 6β-pyridinyl amidomorphines exhibiting long-lasting antinociception.MedChemComm · 2017Article
- 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion.ACS chemical neuroscience · 2016Article
- Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand.European journal of pharmacology · 2014Article
- Design, synthesis, and biological evaluation of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan derivatives as peripheral selective μ opioid receptor Agents.Journal of medicinal chemistry · 2012Article
- 6β-N-heterocyclic substituted naltrexamine derivative NAP as a potential lead to develop peripheral mu opioid receptor selective antagonists.Bioorganic & medicinal chemistry letters · 2012Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Recently, two novel N-heterocyclic derivatives of naltrexone [designated 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)acetamido]morphinan (NAP) and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl) acetamido]morphinan (NAQ)] have been proposed as μ-opioid receptor (MOR) selective antagonists. The goal of this study was to examine their absorption and metabolism. The bidirectional transport of NAP and NAQ was determined in Caco-2 and MDCKII-MDR1 cells, and the permeability directional ratio (PDR) was estimated (PDR = P(app, B-A)/P(app, A-B), where P(app) is the apparent permeability, A is apical, and B is basolateral). Oxidative metabolism of NAQ (0.5-80 μM) and NAP (0.5-30 μM) was determined in pooled human liver microsomes. The reaction monitored the disappearance of NAQ/NAP. NAP and NAQ were quantitated by high-performance liquid chromatography-UV at 270 or 232 nm, respectively. The permeability of NAQ or NAP was similar to that of naltrexone or paracellular markers, respectively. NAP also exhibited a high PDR and was determined to be a P-glycoprotein (P-gp) substrate. Unbound fractions in human plasma for NAQ and NAP were 0.026 ± 0.019 and 0.85 ± 0.12, respectively. The metabolic oxidative reaction rates, fitted to a Michaelis-Menten model, yielded K(m) and V(max) values of 15.8 ± 5.5 μM and 192 ± 24 pmol/min for NAQ and 1.8 ± 1.5 μM and 8.1 ± 1.4 pmol/min for NAP. Intrinsic hepatic clearance was estimated to be 13 and 5 ml · min(-1) · kg(-1) for NAQ and NAP, respectively. Neither NAQ nor NAP underwent detectable glucuronidation. Thus, NAP was a P-gp substrate with low apparent permeability, whereas NAQ was not a P-gp substrate and showed better permeability. Therefore, in contrast to NAP, NAQ would be more suitable for oral absorption and penetration of the blood-brain barrier, yielding potential pharmacokinetic and pharmacodynamic advantages over naltrexone.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.