[3H]U-69593 a highly selective ligand for the opioid κ receptor

Lahti, Robert A.; Mickelson, Mary M.; McCall, John M.; Voigtlander, P. F. Von

doi:10.1016/0014-2999(85)90431-5

Cited by 441 publications

(204 citation statements)

References 7 publications

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“…The most potent indolotropane, endo-3-c I-methylindol-2-yll-g-methyl-gazabicyclo The potencies of ibogaine, O-desmethylibogaine, and 0-t-butyl-0-desmethylibogaine to inhibit f3H]U-69593 binding to brain k-opioid receptors are shown in Table 2. Since radioligand binding to K-opioid receptors varies among species (Lahti et al, 1985). these ligands were examined in membranes from rat.…”

Section: Resultsmentioning

confidence: 99%

“…and O-r-butyl-0desmethylibogaine for these receptors in several species. Interspecies comparisons were made since Lahti et al (1985) have demonstrated differences in the percentage of total opioid binding sites which represent K-opioid sites in rat, mouse and guinea-pig. Consistent with the report of Pearl et al (1995).…”

Section: Discussionmentioning

confidence: 99%

“…and guinea-pig forebrains. The methods employed for tissue preparation and radioligand binding were essentially as described (Lahti et al, 1985). In brief, forebrains were homogenized in ice-cold SO mM Hepes-NH,OH (pH 7.4) and centrifuged at 30000 X g for IO min.…”

Section: Radioligand Binding ['Himk-801mentioning

confidence: 99%

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Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

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Skolnick

Bertha

et al. 1996

European Journal of Pharmacology

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Based on both preclinical findings and anecdotal evidence in man. the psychoactive indole alkaloid ihogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+ )- attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties.kWords:

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

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Skolnick

Bertha

et al. 1996

European Journal of Pharmacology

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“…at 37 ae with TrisHCl, 50 mmol/l, pH 7.4 in polystyrene tubes (Macrowell tube-strips, 12 tubes/strip, Zinsser Analytic GmbH, Frankfurt/Main, Germany). The incubation mixtures contained 0.5 nmol/l of the m-selec- (Cotton et al 1985) or 1.0 nmol/l of the kselective [ 3 H]U69,593 (Lahti et al 1985) in inhibition binding experiments and 0.1-20 nmol/l of the three tritiated opioid agonists in saturation binding experiments. Unlabelled test opioids used to displace these ligands from the particular binding site included DAMGO, DPDPE, U69,593, dihydrocodeine, its metabolites dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O-and dihydromorphine-6-O-glucuronide, nordihydrocodeine and the control ligands morphine, codeine, d,l-methadone and levomethadone.…”

Section: Measurement Of Binding Of the Selective Opioid Agonistsmentioning

confidence: 99%

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Schmidt¹,

Vormfelde

Klinder³

et al. 2002

Pharmacology & Toxicology

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Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O-and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to m-, d-and k-opioid receptors. Codeine, morphine, d,l-methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [ 3 H]DAMGO (m-opioid receptor), [ 3 H]DPDPE (d-opioid receptor) and [ 3 H]U69,593 (k-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the m-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (K i 0.3 mmol/ l), whereas the other metabolites yielded lower affinities. For the d-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (K i 5.9 mmol/ l). In contrast, for the k-opioid receptor, dihydrocodeine-6-O-and dihydromorphine-6-O-glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (K i 14 mmol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6-O-glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O-demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P-450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.The semisynthetic opioid dihydrocodeine is an analgesic and antitussive drug. It exerts its actions by interaction with opioid receptors of different types (m-, d-and k-opioid receptors). Since the beginning of the 1960s dihydrocodeine and dihydrocodeine-containing drugs were used by opioid addicts as a substitute drug to heroin. Recently this use increased by prescribing dihydrocodeine in maintenance treatment of addicts. Individual doses prescribed vary from 60 to 3000 mg dihydrocodeine daily (Frießem & Täschner 1991).Dihydrocodeine, the 7,8-dihydro analogue of codeine, has similar metabolic pathways as codeine (Fromm et al. 1995;Hufschmid et al. 1995). These include O-demethylation to dihydromorphine, formation of the corresponding 6-and/ or 3-O-glucuronides dihydrocodeine-6-O-, dihydromorPart of these results have been presented at

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“…Therefore, KOR is rapidly emerging as an important target for the treatment of a variety of human disorders. At present, KOR agonists have attracted considerable attention because of their abilities to exert potent analgesic effects without high abuse liability [9,10] and to minimize serious MOR-mediated side effects, including respiratory depression and dependence liability [11][12][13] . Delta opioid receptor (DOR) agonists can produce analgesia, but these compounds also have serious side effects, most notably convulsions [14] , that limit their therapeutic development.…”

Section: Introductionmentioning

confidence: 99%

A cell-based, high-throughput homogeneous time-resolved fluorescence assay for the screening of potential κ-opioid receptor agonists

et al. 2014

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Aim: The aim of this study was to identify κ-opioid receptor (KOR) agonists from a library of 80 000 small-molecule compounds and provide the experimental basis for the development of new analgesic candidates. Methods: The cell-based, high-throughput screen for human KOR agonists was based on the LANCE TM cAMP assay. Preliminary structure-activity relationship (SAR) analysis was applied according to the compounds' structures. An acetic acid twisting experiment was used to verify the pharmacodynamics. Results: In total, 31 compounds were identified as KOR agonists after preliminary and secondary screening. Of these compounds, five demonstrated significant KOR-stimulating activity that was comparable to U-50,488, a selective KOR agonist. The EC 50 values for I-7, I-8, I-10, II-5, and II-8 were 13.34±1.65, 14.01±1.84, 9.57±0.19, 14.94±0.64, and 8.74±0.72 nmol/L, respectively. Based on SAR studies, the stimulating activity of compounds with 5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyrimidine (group I) and 3,4-dimethoxy-N-(2-oxoethyl)-N-p-tolylbenzenesulfonamide (group II) parent structures were higher than the compound with a 5-hydroxy-2-methylbenzofuran-3-carboxylic acid (group III) parent structure. Pharmacodynamic experiments indicated that 20-40 μg/kg ip of compounds I-10 and II-8 significantly decreased the number of writhes induced by acetic acid; this finding is consistent with the SAR studies. Furthermore, the analgesic effects of compounds I-10 and II-8 were significantly antagonized in the presence of the selective KOR antagonist nor-BNI. Conclusion: These findings collectively indicate that compounds I-10 and II-8 exhibit significant analgesic activities, providing evidence, at least in part, for their clinical application as new analgesic drugs.

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[3H]U-69593 a highly selective ligand for the opioid κ receptor

Cited by 441 publications

References 7 publications

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

A cell-based, high-throughput homogeneous time-resolved fluorescence assay for the screening of potential κ-opioid receptor agonists

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