RTI-4614-4: An analog of (+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for mu versus delta opioid binding sites

Rothman, Richard B.; Xu, Heng; Seggel, Mark R.; Jacobson, Arthur E.; Rice, Kenner C.; Brine, George A.; Carroll, F. Ivy

doi:10.1016/0024-3205(91)90346-d

Cited by 37 publications

(45 citation statements)

References 14 publications

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“…Mu binding sites were labeled using [ 3 H][D-Ala 2 -MePhe 4 ,Gly-ol 5 ]enkephalin-([ 3 H]DAMGO) (2.0 nM, SA ϭ 45.5 Ci/mmol), and ␦ binding sites were labeled using [ 3 H][D-Ala 2 ,D-Leu 5 ]enkephalin (2.0 nM, SA ϭ 47.5 Ci/mmol) using rat brain membranes prepared as described (Rothman et al, 1991). Kappa binding sites were labeled using [ 3 H]U69,593 (2.0 nM, SA ϭ 45.5 Ci/mmol) and guinea pig brain membranes pretreated with BIT and FIT to deplete the and ␦ binding sites (Rothman et al, 1992).…”

Section: Opioid Binding Assaysmentioning

confidence: 99%

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Xu¹,

Hashimoto²,

Rice³

et al. 2000

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Section: Opioid Binding Assaysmentioning

confidence: 99%

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Xu¹,

Hashimoto²,

Rice³

et al. 2000

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“…Binding affinities for the four [β‐iPrPhe 3 ]DELT analogs were obtained using radiolabeled [ 3 H]‐[ p‐ ClPhe 4 ]DPDPE (δ) (18) and [ 3 H]‐DAMGO (µ) as the ligands (19). Substitution of the different β‐iPrPhe isomers for Phe 3 in DELT I led to large effects on the binding properties of the deltorphin analogs (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, biology, NMR and conformation studies of the topographically constrained δ‐opioid selective peptide analogs of [β‐iPrPhe³]deltorphin I

Liao

Shenderovich

Zhang

et al. 2001

The Journal of Peptide Research

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Replacement of Phe3 in the endogenous delta-opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid beta-isopropylphenylalanine (beta-iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand-binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of [beta-iPrPhe3]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe3 residue in [beta-iPrPhe3]deltorphin I provided the most desirable biological properties with binding affinity (IC50 = 2 nM), bioassay potency (IC50 = 1.23 nM in MVD assay) and exceptional selectivity for the delta-opioid receptor over the mu-opioid receptor (30 000). Further conformational studies based on two-dimensional NMR and computer-assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr1 and (2S,3R)-beta-iPrPhe3 residues adopt trans side-chain conformations, and the linear peptide backbone favors a distorted beta-turn conformation.

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“…Previous studies showed that RTI-4614-4 is a potent and highly selective ligand for the p. opioid receptor (Rothman et al, 1991b). Other experiments (unpublished) established that RTI-4614-4, like (+ )-cis-3methylfentanyl, pseudoirreversibly inhibits p. receptor binding.…”

Section: Discussionmentioning

confidence: 96%

“…Previous studies showed that (* )-cis-N-[l-(2-hydroxy-2-phenylethyl) -3-methyl-4-piperidyll-Nphenylpropanamide HCI (RTI-4614-4) is a potent and highly selective ligand for the p opioid receptor (Rothman et al, 1991b). Although chemically equivalent to ohmefentanyl, RTI-4614-4 is composed of four enantiomers that have been resolved (Brine et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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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RTI-4614-4: An analog of (+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for mu versus delta opioid binding sites

Cited by 37 publications

References 14 publications

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Synthesis, biology, NMR and conformation studies of the topographically constrained δ‐opioid selective peptide analogs of [β‐iPrPhe³]deltorphin I

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

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RTI-4614-4: An analog of (+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for mu versus delta opioid binding sites

Cited by 37 publications

References 14 publications

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Synthesis, biology, NMR and conformation studies of the topographically constrained δ‐opioid selective peptide analogs of [β‐iPrPhe3]deltorphin I

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

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Synthesis, biology, NMR and conformation studies of the topographically constrained δ‐opioid selective peptide analogs of [β‐iPrPhe³]deltorphin I