- New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology
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Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate. Naltrexone, naloxone, and its 14-O-sulfate analogue were used as reference compounds. In competition binding assays, naltrexone-14-O-sulfate showed lower affinity for μ, δ or κ opioid receptor than the parent molecule, naltrexone. However, the μ/κ opioid receptor selectivity ratio significantly improved, indicating better selectivity. Similar tendency was observed for naloxone-14-O-sulfate when compared to naloxone. Naltrexone-14-O-sulfate failed to activate [35S]GTPγS-binding but inhibit the activation evoked by opioid agonists (DAMGO, Ile5,6deltorphin II and U69593), similarly to the reference compounds. Schild plot constructed in MVD revealed that naltrexone-14-O-sulfate acts as a competitive antagonist. In mouse colon, naltrexone-14-O-sulfate antagonized the inhibitory effect of morphine with lower affinity compared to naltrexone and higher affinity when compared to naloxone or naloxone-14-O-sulfate. In vivo (mouse tail-flick test), subcutaneously injected naltrexone-14-O-sulfate antagonized morphine's antinociception in a dose-dependent manner, indicating it's CNS penetration, which was unexpected from such zwitter ionic structure. Future studies are needed to evaluate it's pharmacokinetic profile.
- Zádor, Ferenc,Király, Kornél,Váradi, András,Balogh, Mihály,Fehér, ágnes,Kocsis, Dóra,Erdei, Anna I.,Lackó, Erzsébet,Zádori, Zoltán S.,Hosztafi, Sándor,Noszál, Béla,Riba, Pál,Benyhe, Sándor,Fürst, Susanna,Al-Khrasani, Mahmoud
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- Straight-chain naltrexone ester prodrugs: diffusion and concurrent esterase biotransformation in human skin.
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Naltrexone (NTX) is an opioid antagonist used for treatment of narcotic dependence and alcoholism. Transdermal naltrexone delivery is desirable to help improve patient compliance. The purpose of this study was to increase the delivery rate of NTX across human skin by using lipophilic alkyl ester prodrugs. Straight-chain naltrexone-3-alkyl ester prodrugs of 2-7 carbons in chain length were synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The melting points, solubilities, and skin disposition of the drugs were determined. The prodrugs were almost completely hydrolyzed on passing through the skin and appeared as NTX in the receiver compartment. The mean NTX flux from the prodrug-saturated solutions exceeded the flux of NTX base by approximately 2-7-fold. The amount of drug detected in the skin was significantly greater after treatment with the prodrug solutions compared with treatment with NTX base. The extent of parent drug (NTX) regeneration in the intact skin ranged from 28 to 91%. Higher NTX regeneration percentages in skin appeared to correlate with increased drug delivery rates. Definitively, the highly oil-soluble prodrugs provide a higher NTX flux across human skin in vitro and undergo significant metabolic conversion in the skin. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2571-2578, 2002
- Stinchcomb, Audra L,Swaan, Peter W,Ekabo, Opinya,Harris, Kathleen K,Browe, Jennifer,Hammell, Dana C,Cooperman, Todd A,Pearsall, Michael
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- CRYSTAL OF 6,7-UNSATURATED-7-CARBAMOYL MORPHINAN DERIVATIVE AND METHOD FOR PRODUCING THE SAME
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Stable crystalline forms of a compound represented by the formula (IA): an acid addition salt, and/or a solvate thereof are provided by the present invention. Said crystalline forms are extremely useful as materials for preparing medicines. Novel processes for preparing 6,7-unsaturated-7-carbamoyl morphinan derivatives are also provided by the present invention.
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Paragraph 0217; 0218
(2013/09/12)
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- Process for the preparation of quaternary n-alkyl morphinan alkaloid salts
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An improved process for the N-alkylation of tertiary morphinan alkaloid bases to form the corresponding quaternary morphinan alkaloid derivatives.
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Page/Page column 16; 28-29
(2010/02/17)
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- Process for the Preparation of Quaternary N-Alkyl Morphinan Alkaloid Salts
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An improved process for the N-alkylation of tertiary morphinan alkaloid bases to form the corresponding quaternary morphinan alkaloid derivatives.
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Page/Page column 22
(2010/03/02)
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- SYNTHESIS OF (R)-N-METHYLNALTREXONE
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This invention relates to stereoselective synthesis of R-MNTX and intermediates thereof, pharmaceutical preparations comprising R-MNTX or intermediates thereof and methods for their use.
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Page/Page column 61-62; 5/6
(2010/11/25)
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