Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)- 3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, X-ray analysis, and biological activities.

  title={Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)- 3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, X-ray analysis, and biological activities.},
  author={G. Brine and P. Stark and Y. Liu and F. Carroll and P. Singh and H. Xu and R. Rothman},
  journal={Journal of medicinal chemistry},
  volume={38 9},
(+/-)-cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide (1) is a mixture of four stereoisomers [(2S,3R,4S)-1a, (2R,3R,4S)-1b, (2R,3S,4R)-1c, and (2S,3S,4R)-1d], which together constitute two diastereoisomeric pairs of optical isomers. These four stereoisomers were prepared from optically active intermediates of known absolute configuration by procedures which had no effect on the configurations of the piperidine 3- and 4-carbons. The configuration of the phenylethyl… Expand
(1R)-2-[(3R,4S)-3-Methyl-4-(N-phenyl-N-propionylamino)piperidin-1-yl]-1-phenylethyl p-bromobenzoate and N-[(3R,4S)-1-[(2S)-2-(4-bromophenyl)-2-hydroxyethyl]-3-methyl-piperidin-4-yl]-N-phenylacrylamide.
Both title compounds are brominated derivatives of the potent opioid cis-beta-hydroxy-3-methylfentanyl and have the same stereochemistry at two of the three asymmetric C atoms. Expand
Fentanyl and its analogue N-(1-phenylpyrazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl]propanamide: 1H- and 13C-NMR spectroscopy, X-ray crystallography, and theoretical calculations.
The oxalate salts and free bases of fentanyl and N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide, a new lead compound for long-acting analgesia, have been characterized by (1)H-Expand
Two-step synthesis of new 1,2,4,5-tetrahydrospiro-[3H-2-benzazepine-3,4′-piperidines] from 4-iminopiperidines
New spiro[3H-2-benzazepine-3,4′-piperidines] and their precursors, N-substituted 4-allyl-4-N-benzyl-aminopiperidines, have been prepared as potential psychotic agents from readily availableExpand
2-Substituted 4-anilinopiperidines from 2H-thiopyran-2-thiones
Abstract 4-Dimethylamino-5,6-dihydro-2 H -thiopyran-2-thiones were converted to 4-anilinodihydropyridine-2(1 H )-thiones in several steps. The latter were alkylated giving a mixture of isomericExpand
The flexible molecular docking was used to study interactions between a series of 3,6-diazabicyclo[3.1.1]heptanes, 9,10-diazatricyclo[]decanes, and 2,7-diazatricyclo []decanesExpand
Syntheses, biological evaluation, and molecular modeling of 18F-labeled 4-anilidopiperidines as mu-opioid receptor imaging agents.
In vivo and in vitro data indicate that 18F-labeled 4-anilidopiperidines hold promise for studying the mu-opioid receptor in humans by means of positron emission tomography. Expand
Characterization and Differentiation of Geometric Isomers of 3‐methylfentanyl Analogs by Gas Chromatography/Mass Spectrometry, Liquid Chromatography/Mass Spectrometry, and Nuclear Magnetic Resonance Spectroscopy
The cis and trans isomers of 3‐methylfentanyl and its three analogs were chemically synthesized, and these compounds were characterized and differentiated by gas chromatography/mass spectrometryExpand
The synthesis of a novel analogue of fentanyl, 3-carbomethoxy fentanyl or "iso-carfentanil" has been accomplished in five steps, by simple and efficient route, starting from phenethyl amine andExpand
Opioid peptide receptor studies. 7. The methylfentanyl congener RTI‐4614‐4 and its four enantiomers bind to different domains of the rat μ opioid receptor
It is suggested that the region from the N terminal to the start of the TMH3 of the μ 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 thebinding affinity of μ agonist peptides. Expand
The synthesis of lactam analogues of fentanyl
Fentanyl, sufentanil and alfentanil are clinically widely used anaesthetics and are structurally related to drugs with entirely different pharmacological activity such as droperidol, loperamide andExpand


Synthesis and spectral analysis of (±)-cis-N-[1-(2-hydroxy-2-phenyl-ethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide
Treatment of (±)-cis-N-(3-methyl-4-piperidyl)-N-phenylpropanamide (2) with styrene oxide (1) yielded a mixture of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (3)Expand
Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide.
The synthesis of the respective diastereoisomers and enantiomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidylj-Nphenylpropanamide and N-phenyl Propanamide is reported, which are found to be an extremely potent analgesic, up to 6684 times morphine. Expand
N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin.
R 30 730 has a rapid onset of action and is 4521 times more potent than morphine at the time of peak effect; it has a relatively short duration of action comparable to that of fentanyl and its safety margin is unusually high. Expand
Probes for narcotic receptor mediated phenomena. 12. cis-(+)-3-Methylfentanyl isothiocyanate, a potent site-directed acylating agent for delta opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity.
The first enantiomeric pair of irreversible opioid ligands [(+)- and (-)-4] were synthesized in greater than 99.6% optical purity as determined by HPLC analysis of diastereoisomeric derivatives ofExpand
RTI-4614-4: an analog of (+)-cis-3-methylfentanyl with a 27,000-fold binding selectivity for mu versus delta opioid binding sites.
The objective of this study was to determine the binding affinities of (+/-)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]- N-phenylpropanamide-HCI (RTI-4614-4), which is an analog ofExpand
(+)-Cis-3-methylfentanyl and its analogs bind pseudoirreversibly to the mu opioid binding site: Evidence for pseudoallosteric modulation
The authors speculate that this property, termed "pseudoirreversible inhibition", might contribute to the extraordinary potency of (+)-cis-3-methylfentanyl and its analogs as antinociceptive agents. Expand
Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives.
The result shows that the analgesic potency of the derivatives of this series is mainly dependent on binding affinity for opiate receptor. Expand
Interaction of endogenous opioid peptides and other drugs with four kappa opioid binding sites in guinea pig brain
Quantitative autoradiographic studies demonstrated that kappa 2a and kapp 2b binding sites are heterogeneously distributed in guinea pig brain, and that the anatomical distribution of kappa 1 binding sites reported in the literature is different from that observed in this study for the kappa2 binding sites. Expand
Ohmefentanyl--a new agonist for mu-opiate receptor.
  • H. Xu, J. Chen, Z. Chi
  • Medicine
  • Scientia Sinica. Series B, Chemical, biological, agricultural, medical & earth sciences
  • 1985
Comparison of the relative potencies of morphine, DSTLE and ohmef fentanyl in competing with 3H-dihydromorphine (mu) and 3H-[D-Ala2, D-Leu5]-enkephalin (delta) binding to crude synaptic plasma membranes of mice brain shows that the inhibitory potencies are higher than expected, suggesting that Ohmefentanyl has potent mu-agonist properties. Expand
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
The present study determined the stereochemical requirements for pseudoirreversible inhibition of μ receptor binding using the methylfentanyl congeners, (±)‐cis‐N‐[1‐(2hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]‐n‐phenylpropanamide HCI and its four resolved enantiomers, and proposed a pseudoallosteric model. Expand