The potent opioid agonist, (+)-cis-3-methylfentanyl binds pseudoirreversibly to the opioid receptor complex in vitro and in vivo: Evidence for a novel mechanism of action

Band, Linda C.; Xu, Heng; Bykov, Victor; Greig, Nigel H.; Kim, Chong-Ho; Newman, Amy Hauck; Jacobson, Arthur E.; Rice, Kenner C.; Rothman, Richard B.

doi:10.1016/0024-3205(90)90154-j

Cited by 7 publications

(6 citation statements)

References 17 publications

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“…Second, we have previously reported a decrease in µ-opioid binding sites without changes in the affinity in brain membrane homogenates from animals submitted to an identical protocol of chronic sufentanil treatment (Díaz et al 1995b). A decrease in the specific binding due to the presence of unwashed opioid should have been associated also to changes in the affinity (Band et al 1990), which was not the case. Finally, animals treated with an acute dose of sufentanil (0.5 µg/kg, s.c.) did not display any change in receptor density either in brain homogenates (Díaz et al 1995b) or in brain sections (data not shown).…”

Section: Discussionmentioning

confidence: 94%

Autoradiographic mapping of µ-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system

Díaz

Pazos

Flórez

et al. 2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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In this autoradiographic study we have analysed the regional changes in the density of mu-opioid receptors produced by the chronic administration of sufentanil alone and after concurrent administration with nimodipine. mu-Opioid receptors in the central nervous system (CNS) of rats were labelled using 5 nM [3H]DAMGO. Sufentanil, a high-efficacy agonist, was administered for 7 days by chronic infusion (2 microg/h). Another group of animals received a simultaneous infusion of sufentanil (2 microg/h) and nimodipine (1 microg/h) for 7 days. These two drug regimes have been previously shown to induce tolerance and supersensitivity to the analgesic effect of the opioid, respectively. Our results clearly demonstrate that opioid tolerance is associated with a generalised down-regulation of mu-opioid binding sites throughout the brain and the spinal cord. Compared with the findings in tolerant animals, the CNS of animals supersensitive to sufentanil showed less down-regulation of mu-opioid receptors, to the extent that, particularly in brain areas related to nociception, such as the somatosensory cortex, central grey, raphe magnus nucleus and dorsal horn of the spinal cord, no down-regulation occurred. These neurochemical findings may contribute to the functional interaction between nimodipine and sufentanil that we have previously observed in analgesic studies.

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Section: Discussionmentioning

confidence: 94%

Autoradiographic mapping of µ-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system

Díaz

Pazos

Flórez

et al. 2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…For example, as illustrated in Figure 5, the decrease in steady-state binding follows the rank-order of [3HlDAMG0 > r3H1fentanyl > i3H]etorphine, whereas the alteration in dissociation kinetics follows the reverse order, with there being no alteration at all in r3H]DAMG0 dissociation. A model consistent with these data is one that postulates that the drug recognition site of the p receptor is composed of overlapping domains (Xu et al, 1991;Band et al, 1990). That is, different p ligands do not necessarily bind to precisely the same topographic regions of the recognition site.…”

Section: Discussionmentioning

confidence: 69%

“…Previous studies from this laboratory established that ( + )-cis-3-methylfentanyl pseudoirreversibly inhibited opioid p receptor binding in vivo (Band et al, 1990) and in vitro (Xu et al, 1991). Although the simplest explanation for this phenomenon would be occlusion of the p. recognition site by (+)-cis-3-methylfentanyl, the data indicated a more complex mechanism (Xu et al, -4614-4, lb, and lc on the specific binding of L3H1DAMGO, [3Hlfentanyl, and [3Hletorphine is summarized. 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Another interesting property of (+)-3-methylfentanyl and its congeners is their ability to act as pseudoirreversible inhibitors of p receptor binding, both in vitro (Xu et al, 1991) and in vivo (Band et al, 1990). For example, preincubation of membranes with ( + )-cis-% methylfentanyl or ohmefentanyl, followed by an extensive washing procedure, produced an apparently irreversible inhibition of p receptor binding.…”

Section: Introductionmentioning

confidence: 99%

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Stereochemical requirements for pseudoirreversible inhibition of opioid mu receptor binding by the 3‐methylfentanyl congeners, RTI‐46144 and its enantiomers: Evidence for different binding domains

Partilla

et al. 1993

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Fentanyl and its congeners are of interest not only because of their clinical applications, but also because certain members of this series of opioid analgesics exhibit unique properties, such as acting as pseudoirreversible inhibitors of mu receptor binding, both in vitro and in vivo. Previous studies showed that pretreatment of membranes with (+)-cis-3-methylfentanyl resulted in a lower affinity interaction of [3H]ohmefentanyl with the mu binding site, as well as an increased dissociation rate. The present study was undertaken to determine the stereochemical requirements for pseudoirreversible inhibition of mu receptor binding using the methylfentanyl congeners, (+-)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide HCl (RTI-4614-4) and its four resolved enantiomers. AR configuration of the 2-hydroxy group was essential for high affinity binding and pseudoirreversible inhibition. The two enantiomers with this configuration, 1b((2R,3R,4S)-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide oxolate) and 1c 1c ((2R,3S,4R)-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide HCl), acted as pseudoirreversible inhibitors of the mu receptor as labeled with [3H][D-Ala2-MePhe4,Gly-ol5]enkaphalin, [3H]fentanyl or [3H]etorphine. RTI-4614-4, 1b, and 1c decreased the Bmax of [3H][D-Ala2-MaePhe4,Gly-ol5]enkepalin binding sites without altering the dissociation rate. These drugs had a lesser effect on steady-state [3H]fentanyl and [3H]etorphine binding but did produce statistically significant changes in the parameters of the two-component dissociation model, which accurately described the dissociation of these [3H]ligands. Viewed collectively, these data indicate that the mechanism of the pseudoirreversible inhibition appears to depend on the radioligand used to label the mu receptor. To explain these data, a pseudoallosteric model is proposed that postulates that certain mu ligands bind to different domains of the drug recognition site of the mu receptor and that the prebinding of pseudoirreversible inhibitors to the recognition site changes the domains available to a radioligand, leading to alterations in steady-state binding levels and dissociation kinetics.

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“…Another interesting property of (ϩ)-3-methylfentanyl and its congeners is their ability to act as pseudoirreversible inhibitors of µ receptor binding both in vitro and in vivo (Band et al, 1990). Preincubation of membranes with (ϩ)-cis-3-methylfentanyl or ohmefentanyl, followed by an extensive washing procedure, resulted in apparent irreversible inhibition of µ receptor binding.…”

Section: Introductionmentioning

confidence: 99%

Opioid peptide receptor studies. 7. The methylfentanyl congener RTI-4614-4 and its four enantiomers bind to different domains of the rat ? opioid receptor

Liu-Chen

et al. 1998

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Mutational analysis of opioid receptors supports the hypothesis that dissimilar receptor domains contribute to the binding affinity of different ligands. To determine whether enantiomeric ligands can serve to distinguish between different binding pockets (which focuses the analysis on asymmetric structural factors while avoiding confounding changes in physiochemical characteristics), we analyzed the binding of the 3-methylfentanyl congeners RTI-4614-4 [(+/-)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide HCl)], its four stereoisomers [(2S,3R,4S)-1a, (2R,3R,4S)-1b, (2R,3S,4R)-1c, and (2S,3S,4R)-1d], and other mu agonists with cloned rat mu opioid receptors stably expressed in HEK-293 cells and mu/kappa receptor chimeras. Chimera III (kappa[aminoacids 1-141]/mu[aminoacids 151-398]), chimera IV (mu[aminoacids 1-150]/kappa[aminoacids 142-380]), and chimera XII (kappa[aminoacids 1-262]/mu[aminoacids 269-398]) bound [(125)I]IOXY (6beta-iodo-3,14-dihydoxy-17-cyclopropylmethyl-4,5alpha++ +-epoxymorphinan) with high affinities. The Ki values of 1a, 1b, 1c, and 1d at the wild-type mu receptor were 0.55 nM, 0.66 nM, 124 nM, and 59.2 nM, respectively. When the region from the N terminal to the start of the transmembrane helix 3 (TMH3) of the mu receptor was substituted by that of the kappa receptor (chimera III), the Ki value of 1b was increased (relative to the mu receptor) 590-fold compared to a 73-fold increase for 1a. When this portion of the kappa receptor was replaced by that of the mu receptor (chimera IV), the loss of affinity was not as great: 11.7-fold for 1a and 58.5-fold for 1b. Replacement of the middle of the third intracellular loop and third extracellular loop (e3) of the kappa receptor with that of the mu receptor (chimera XII) lowered (relative to their Ki values at the kappa receptor) the Ki values of [D-Ala2,D-Leu5]enkephalin and [D-Ala2-MePhe4,Gly-ol5]enkephalin to a much greater extent than the Ki values of the isomers. The kappa/chimera XII shift was greater for isomers 1c and 1d than for 1b and 1a. Viewed collectively, these data suggest that the region from the N terminal to the start of the TMH3 of the mu opioid receptor determines the binding affinity of RTI-4614-4 and its isomers and that the e3 loop also plays a major role in determining the binding affinity of mu agonist peptides. These data also show that the stereoisomers of RTI-4614-4 probably bind to different domains of the mu receptor and suggest that manipulation of stereochemistry may be a useful tool for designing domain-specific ligands.

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The potent opioid agonist, (+)-cis-3-methylfentanyl binds pseudoirreversibly to the opioid receptor complex in vitro and in vivo: Evidence for a novel mechanism of action

Cited by 7 publications

References 17 publications

Autoradiographic mapping of µ-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system

Autoradiographic mapping of µ-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system

Stereochemical requirements for pseudoirreversible inhibition of opioid mu receptor binding by the 3‐methylfentanyl congeners, RTI‐46144 and its enantiomers: Evidence for different binding domains

Opioid peptide receptor studies. 7. The methylfentanyl congener RTI-4614-4 and its four enantiomers bind to different domains of the rat ? opioid receptor

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