Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive study on cyprodime-related compounds

Schmidhammer, Helmut; Smith, C. F. C.; Erlach, Daniela; Koch, Martin; Kraßnig, Roland; Schwetz, Wolfgang; Wechner, Christine

doi:10.1021/jm00166a018

Cited by 44 publications

(22 citation statements)

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“…This finding is consistent with binding studies indicating that NorBNI has little affinity for K2 binding sites (Neck et al, 1988(Neck et al, , 1990(Neck et al, , 1993Zukin et al, 1988;Rothman et al, 1992). In addition, the p-selective antagonist cyprodime (Schmidhammer et al, 1990) and the S-selective antagonist naltrindole (Contreras et al, 1993) also had no effect on the inhibitory actions of bremazocine (Fig. 5s).…”

Section: Resultssupporting

confidence: 90%

Kappa 2 opioid receptors inhibit NMDA receptor-mediated synaptic currents in guinea pig CA3 pyramidal cells

1994

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The role of the endogenous opioid peptide dynorphin (1–17) in regulating NMDA receptor-mediated synaptic currents was examined in guinea pig hippocampus. Schaffer collateral/commissural fiber-evoked NMDA synaptic currents were recorded using whole-cell patch-clamp techniques in CA3 pyramidal cells. Dynorphin was found to have dual effects on NMDA synaptic currents, increasing currents at low concentrations and decreasing currents at high concentrations. Only the inhibitory action of dynorphin was sensitive to naloxone, indicating that this effect was mediated by an opioid receptor. The inhibitory effect was mimicked by bremazocine, but not by U69,593, U50,488, [D- Ala2, N-Me-Phe4, Gly-ol]-enkephalin, or [D-Pen2,5]-enkephalin. Bremazocine's effect was blocked by naloxone, but not by nor- binaltorphimine, cyprodime, or naltrindole. These findings suggest that bremazocine's effect was mediated by the kappa 2 subtype of opioid receptor. In addition, 1 microM naloxone and antisera to dynorphin (1– 17) were found to increase NMDA-mediated synaptic currents. Nor- binaltorphimine, cyprodime, naltrindole, and antisera to met-enkephalin did not increase the NMDA synaptic current. These findings suggest that endogenous dynorphin was acting at kappa 2 receptors to inhibit NMDA receptor-mediated synaptic currents. Overall, these findings indicate that dynorphin is an endogenous agonist for kappa 2 receptors in the CA3 region of the guinea pig hippocampus and that these receptors regulate NMDA receptor function.

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Section: Resultssupporting

confidence: 90%

Kappa 2 opioid receptors inhibit NMDA receptor-mediated synaptic currents in guinea pig CA3 pyramidal cells

1994

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“…O-methylation was carried out by dimethyl sulfate in the presence of sodium hydride in N,N-dimethylformamide (Kobylecki et al, 1982;Razdan and Ghosh, 1980). 14-O-methylcodeinone was selectively demethylated in the 3-O position by refluxing in aqueous hydrogen bromide (Schmidhammer et al, 1990 6, 138.6, 137.8, 132.8, 129.0, 126.2, 119.5, 117.1, 90.2, 74.9, 66.0, 57.4, 50.6, 47.6, 46.0, 43.3, 30.6, 29.9, 22.6 ppm. …”

Section: Chemistrymentioning

confidence: 99%

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Zádor

Balogh

Váradi

et al. 2017

European Journal of Pharmacology

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A B S T R A C T14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-OMeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. binding. In addition, 14-O-MeM compared to morphine showed higher affinity for μ-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value.

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“…[19,20] Furthermore in the mouse vas deferens bioassay, cyprodime exhibited improved mu opioid receptor selectivity in compari- . [20,21] trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines and conformationally constrained analogues…”

Section: Morphinansmentioning

confidence: 99%

“…[21] Introduction of a methyl substituent at the 3-position of the opioid agonist 16 [23] was investigated ( Figure 4). This structural modification led to the identification of compound 17, which displayed pure antagonist activity in vivo.…”

Section: Morphinansmentioning

confidence: 99%

Mu Opioid Receptor Antagonists: Recent Developments

2007

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For thousands of years mu opioid agonists such as morphine have been utilized for their analgesic properties. Today, morphine and related compounds are still used as a first line therapy in the treatment of moderate to severe pain. However, despite the clear benefits of mu agonists in pain management, severe side effects such as dependence and respiratory depression are associated with use of these drugs. To date, there are only two approved mu opioid antagonists for use in the treatment of these adverse effects, that is, naloxone and naltrexone. However, many other clinical and therapeutic areas have been linked to mu opioid receptor antagonism. These include treatment of opioid induced pruritis of the skin, obesity, and Parkinson‐induced tardive dyskinesia. Currently there are two compounds, N‐methylnaltrexone and alvimopan, under FDA review as possible treatments for opioid induced bowel dysfunction and postoperative ileus. These compounds are of special interest as they are peripherally restricted. This attribute enables treatment of peripheral side effects induced by opioid agonists without reversal of the centrally mediated analgesia of the agonist. In this article we discuss the structural classes of mu opioid antagonists, their potential clinical applications, and review the relevant patents of the last ten years.

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Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive study on cyprodime-related compounds

Cited by 44 publications

References 0 publications

Kappa 2 opioid receptors inhibit NMDA receptor-mediated synaptic currents in guinea pig CA3 pyramidal cells

Kappa 2 opioid receptors inhibit NMDA receptor-mediated synaptic currents in guinea pig CA3 pyramidal cells

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Mu Opioid Receptor Antagonists: Recent Developments

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