Preparation OF [7, 8, 19, 20 ‐ <sup>3</sup>H] Naloxone of high specific activity

Tóth, Géza; Kramer, Mark S.; Sirokmán, F.; Borsodi, Anna; Rónai, A. Z.

doi:10.1002/jlcr.2580190904

Cited by 50 publications

(4 citation statements)

References 9 publications

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“…For comparison of quantitative ORL1 binding, two way anova (for factors genotype and region) was carried out followed by post hoc analysis of individual regions using Dunnett's test. [ 3 H]naloxone (28 Ci/mmol) was synthesized by Hungarian Academy of Sciences, Szeged according to the method of Toth et al . (1982).…”

Section: Methodsmentioning

confidence: 99%

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice

Clarke

Czyzyk

Ansonoff

et al. 2002

Eur J of Neuroscience

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Three genes for the opioid receptors ( micro, delta and kappa) and a gene coding for a related receptor (ORL1) have been cloned but pharmacological studies suggest that further subtypes exist that remain poorly understood. To determine if there are other classically defined opioid binding sites we have carried out homogenate binding and section autoradiography with [3H]naloxone in mice that lack all three opioid genes and are hyperalgesic in a thermal nociceptive test. We have also examined [3H]bremazocine labelling in triple knockout brain and spinal cord as this ligand has been proposed to label novel kappa-receptors. No receptor labelling for either ligand was detected in the brains or spinal cord of knockout mice demonstrating that all binding is the product of the three known receptors and that there is no cross-labelling of the ORL1 receptor. Nociceptin (1 micro m) caused marked displacement of [3H]bremazocine in wild-type brains indicating that nociceptin at high concentrations can displace classical opioid binding. As a number of studies have proposed a close association between the classical opioid receptors and the ORL1 system we also hypothesized that loss of all of the classical opioid receptors might lead to compensatory changes in ORL1 receptors. Labelling of the ORL1 receptor with [3H]nociceptin showed region-dependent quantitative increases in triple knockout brains indicating a close relationship between the two systems in specific brain areas.

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Section: Methodsmentioning

confidence: 99%

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice

Clarke

Czyzyk

Ansonoff

et al. 2002

Eur J of Neuroscience

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“…Over the years, we have performed this robust reaction numerous times and display a typical proton decoupled tritium NMR of [N‐allyl‐ 3 H]naloxone (CDCl 3 ) in Figure . At just the same time, Toth and co‐workers independently and creatively combined both of these approaches to tritiate naloxone at the highest specific activity yet reported, 83.7 Ci/mmol, as shown in Scheme . They first prepared [7, 8‐ 3 H]noroxymorphone ( 17 ), as did Fishman, but then converted it to [7, 8‐ 3 H]N‐propargylnoroxymorphone ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Morphinan alkaloids labeled with tritium: synthesis and applications

Filer

2013

Labelled Comp Radiopharmac

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“…The in vitro effect produced by Na ions on opioid-binding [15] in displacement experiments with [ 3 H]naloxone [16] was used ( Table 2). According to their Na indices, all new ligands, except 4, were antagonists.…”

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“…layer was washed with H 2 O (3Â 60 ml), dried (Na 2 SO 4 ), and evaporated to give a brown foam (0.36 g), which was converted to the methanesulfonate in the usual way: 0. 17-(Cyclopropylmethyl)-4,5a-epoxy-14b-ethoxy-3-(methoxymethoxy)benzofuro[2',3':6,7]morphinan (16). A mixture of 15 [12] (300 mg, 0.64 mmol), NaH (36 mg, 1.50 mmol; obtained from 60% NaH dispersion (60 mg) in oil by washing with hexane), and anh.…”

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confidence: 99%

Novel Delta-Opioid-Receptor-Selective Ligands in the 14-Alkoxy-Substituted Indolo- and Benzofuromorphinan Series

Biyashev

Monory

Benyhe

et al. 2001

HCA

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Several new indolo-and benzofuromorphinans substituted at the positions 5 and 14 were prepared and tested in vitro by means of opioid-receptor binding and functional ([ 35 S]GTPgS binding) assays. All compounds 1 ± 11 displayed high affinity for d opioid-binding sites ( Table 1). Compound 4 proved to be an agonist, and all other compounds were antagonists. The presence of a Me group at position 5 induced no change in d affinity (see 1 vs. 3), but decreased the m and k affinities. An EtO group at position 14 conferred a very high affinity and also high selectivity to d opioid receptors (see 2 and 10). Chain elongation of the 14-alkoxy group resulted in compounds with reduced d affinity and selectivity (see 4 and 11 and also 5 ± 9). The results of the present study indicate that the 5-and 14-positions of indolo-and benzofuromorphinans represent critical sites that could be a trigger to develop new compounds with increased d affinity and/or selectivity.Introduction. ± Opioid agonists acting through m opioid receptors (one of the three commonly accepted major classes of opioid receptors [1]) are used clinically for pain treatment. However, they can cause severe side effects such as respiratory depression, constipation, nausea, vomiting, and, moreover, their chronic use results in tolerance and dependence [2]. The clinical use of k opioid agonists is very much limited due to their dysphoric and psychotomimetic properties [3]. d Opioid agonists, while having analgesic properties, induce weaker physical dependence [4]. Therefore, d opioidreceptors appear to represent important therapeutic targets for the development of novel safer analgesic agents [5]. It was shown that d opioid receptors are involved in the regulation of the immune system [6]. While d agonists tend to be immunostimulants, d antagonists display potent immunosuppressive activity. There are also data suggesting that d opioid antagonists can be used for treatment of alcohol and drug addiction [7].Among the ligands acting at d opioid receptors, there are peptides as well as nonpeptide opioid compounds. Nonpeptide opioids are preferred as pharmacological tools, since they can generally penetrate the central nervous system and are less subject to metabolic degradation. There is much emphasis on the development of new selective antagonists that, except for medicinal purposes, can be also used to evaluate the selectivity of new agonists and to study the interaction of endogenous ligands with different opioid receptors [8]. By means of the message-address concept, selective opioid ligands with antagonist activity were developed. Based on the naltrexone structure, the addition of an address element, such as an indole or benzofuran moiety, resulted in two d-selective antagonists, naltrindole (NTI) and naltriben (NTB), respectively [9].

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Preparation OF [7, 8, 19, 20 ‐ ³H] Naloxone of high specific activity

Cited by 50 publications

References 9 publications

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice

Morphinan alkaloids labeled with tritium: synthesis and applications

Novel Delta-Opioid-Receptor-Selective Ligands in the 14-Alkoxy-Substituted Indolo- and Benzofuromorphinan Series

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Preparation OF [7, 8, 19, 20 ‐ 3H] Naloxone of high specific activity

Cited by 50 publications

References 9 publications

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice

Morphinan alkaloids labeled with tritium: synthesis and applications

Novel Delta-Opioid-Receptor-Selective Ligands in the 14-Alkoxy-Substituted Indolo- and Benzofuromorphinan Series

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Preparation OF [7, 8, 19, 20 ‐ ³H] Naloxone of high specific activity