[3H]sufentanil, a superior ligand for μ-opiate receptors: Binding properties and regional distribution in rat brain and spinal cord

Leysen, Josée E.; Gommeren, W.; Niemegeers, C. J. E.

doi:10.1016/0014-2999(83)90331-x

Cited by 226 publications

(76 citation statements)

References 14 publications

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“…The strongest relationship observed was between unbound brain EC 50,u and K i (r 2 Ͻ 0.799). Leysen et al (1983). b Terenius (1975).…”

Section: Resultsmentioning

confidence: 99%

“…Leysen et al (1983) reported a correlation (r 2 ϭ 0.81) between in vitro K i (displacement of sufentanil in rat forebrain membranes) and ED 50 (rat tail withdrawal reflex) for 35 opioids from five structural classes, with Ͼ100,000-fold difference in receptor affinity. However, no correlation existed between K i and ED 50 if only the seven opioids from this study were included in their analysis (r 2 Ͻ 0.15) (Niemegeers et al, 1979;Leysen et al, 1983). Results from this study show a similarly poor correlation (r 2 ϭ 0.167) between in vitro K i and mouse ED 50 .…”

Section: Discussionmentioning

confidence: 99%

“…Often, this is the case, and significant correlations between in vivo ED 50 or EC 50 and in vitro potency have been established for a variety of therapeutic targets (Leysen et al, 1983;Visser et al, 2003). However, when there is no correlation between in vivo and in vitro potency measures, the validity of the in vitro assay, the animal model, and the target may be questioned.…”

mentioning

confidence: 99%

“…Seven -opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as probe CNS drugs. These agents were selected on the bases of having pronounced differences in potency toward the -opioid receptor (Terenius, 1975;Leysen et al, 1983), differing physiochemical properties (i.e., lipophilicity, unbound fractions, and permeability), and differing extent of CNS distribution (i.e., P-gp or non-P-gp substrate) (Dagenais et al, 2004). PK/PD studies were conducted in mice to determine five measures of in vivo potency (ED 50 ; total and unbound EC 50 for both serum and brain) for each opioid.…”

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC_50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Kalvass

Olson²,

Cassidy³

et al. 2007

J Pharmacol Exp Ther

150

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This study was conducted to assess the utility of unbound brain EC 50 (EC 50,u ) as a measure of in vivo potency for centrally active drugs. Seven -opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as model central nervous system drugs because they elicit a readily measurable central effect (antinociception) and their clinical pharmacokinetics/pharmacodynamics are well understood. Mice received an equipotent subcutaneous dose of one of the model opioids. The time course of antinociception and the serum and brain concentrations were determined. A pharmacokinetic/pharmacodynamic model was used to estimate relevant parameters. In vitro measures of opioid binding affinity (K i ) and functional activity [EC 50 for agonist stimulated guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding] and relevant clinical parameters were obtained to construct in vitro-to-preclinical and preclinical-to-clinical correlations. The strongest in vitro-to-in vivo correlation was observed between K i and unbound brain EC 50,u (r 2 ϳ 0.8). A strong correlation between mouse serum and human plasma EC 50 was observed (r 2 ϭ 0.949); the correlation was improved when corrected for protein binding (r 2 ϭ 0.995). Clinical equipotent i.v. dose was only moderately related to K i . However, estimates of ED 50 and EC 50 (total serum, unbound serum, total brain, and unbound brain) were significant predictors of clinical equipotent i.v. dose; the best correlation was observed for brain EC 50,u (r 2 ϭ 0.982). For each opioid, brain equilibration half-life in mice was almost identical to the plasma effect-site equilibration half-life measured clinically. These results indicate that the mouse is a good model for opioid human brain disposition and clinical pharmacology and that superior in vitro-to-preclinical and preclinicalto-clinical correlations can be achieved with relevant unbound concentrations.In drug discovery, in vitro assays and preclinical animal studies are widely used to assess compound potency and to identify compound(s) that may have a desirable clinical response. Several options for assessing compound potency are available, including in vitro (receptor binding or functional assays) and in vivo (animal studies to determine dose-response or concentration-response relationships) protocols. In vitro binding and functional assays, by nature, are designed to estimate the intrinsic affinity or potency at the receptor of interest, whereas in vivo experiments take into account the full spectrum of pharmacokinetic and pharmacodynamic processes that ultimately determine biological response.Ideally, in vitro potency would translate to or predict in vivo potency. Often, this is the case, and significant correlations between in vivo ED 50 or EC 50 and in vitro potency have been established for a variety of therapeutic targets (Leysen et al., 1983;Visser et al., 2003). However, when there is no correlation between in vivo and in vitro potency measures, the validity of the in vitro as...

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“…The strongest relationship observed was between unbound brain EC 50,u and K i (r 2 Ͻ 0.799). Leysen et al (1983). b Terenius (1975).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC_50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Kalvass

Olson²,

Cassidy³

et al. 2007

J Pharmacol Exp Ther

150

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“…For serotonin (S,) receptors the conditions were as described in 1241 and for opiate receptors as described in [25]. Fig.…”

Section: Binding Assaysmentioning

confidence: 99%

Photoaffinity labelling of dopamine receptors

Wouters¹,

Dun²,

Laduron³

1984

European Journal of Biochemistry

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A new compound, azapride, i.e. 4-azido-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide, the azide derivative of the dopamine antagonist clebopride, was synthesized and tested for its usefulness as a photoaffinity probe for dopamine receptors. Without photolysis the azide behaved as a very selective dopamine antagonist. When a microsomal preparation of dog striatum was pretreated with the azide and subsequently irradiated with ultraviolet light, dopamine receptors became irreversibly blocked. This reaction was dependent on both azide concentration and time of irradiation. The irradiation-induced inhibition was quite selective for the dopamine receptor; various other receptor systems were not affected. Moreover the irreversible inhibition of dopamine receptors from dog striatum could be prevented by dopamine antagonists as well as by a dopamine agonist, but not by a serotonin antagonist. The irradiation-induced inactivation by azapride remained unchanged in the presence of the scavenger p-aminobenzoic acid.These findings provide evidence that azapride labels dopamine receptors specifically and irreversibly and by a true photoaffinity mechanism. It should therefore be of great value for further molecular characterization and purification of dopamine receptors.The identification of brain dopamine receptors has been closely associated with the development of neuroleptic drugs: they were for the dopamine receptor what cc-bungarotoxin was for the nicotinic receptor [l]. Indeed, in contrast to hormones and neuropeptides, classical neurotransmitters (acetylcholine, dopamine, 5-hydroxytryptamine, noradrenaline, etc) cannot be used to characterize receptor sites in vitro because of their very low affinity and rapid rate of dissociation 121.Biochemical and pharmacological studies first suggested the existence of dopamine receptors 13, 41; more direct evidence for this was provided when [3H]haloperidol [5, 61 and [3H]spiperone [7] were reported to label brain dopamine receptors in binding assays in vitro. Although [3H]spiperone also binds to serotonin S, receptors [S], a fact which is not a disadvantage if selective displacers are used, it is one of the most widely used ligands and the most appropriate for binding in vivo and solubilization studies 19, 101.High-affinity dopamine receptors were first obtained in soluble form from dog striaturn with digitonin as detergent and 13H]spiperone as ligand [I I]. More recently, brain dopamine receptors from different species were solubilized using a mixture of cholate and salt [12, 131. Since, until now, the attempts to purify dopamine receptors using conventional techniques were unsuccessful, another approach to dismantle the molecular structure of the dopamine receptor seems to be required.Photoaffinity probes have been developed for several receptors 114 -171 and have thus largely contributed to the elucidation of numerous receptor systems. Photoaffinity probes have the advantage over other affinity probes that they are applied in a two-stage system; first they are...

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Analgesics and Antipyretics

Friderichs

Christoph

Buschmann

2007

Ullmann's Encyclopedia of Industrial Chemistry

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[3H]sufentanil, a superior ligand for μ-opiate receptors: Binding properties and regional distribution in rat brain and spinal cord

Cited by 226 publications

References 14 publications

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC_50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC_50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Photoaffinity labelling of dopamine receptors

Analgesics and Antipyretics

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[3H]sufentanil, a superior ligand for μ-opiate receptors: Binding properties and regional distribution in rat brain and spinal cord

Cited by 226 publications

References 14 publications

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Photoaffinity labelling of dopamine receptors

Analgesics and Antipyretics

Contact Info

Product

Resources

About

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC_50,uand Correlation of in Vitro, Preclinical, and Clinical Data

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC_50,uand Correlation of in Vitro, Preclinical, and Clinical Data