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

Bever, Willem F. M. Van; Niemegeers, C. J. E.; Janßen, Paul

doi:10.1021/jm00256a003

Cited by 150 publications

(67 citation statements)

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“…Second, chimeras /␦1 and ␦/3 may assume favorable conformations for SUPERFIT to form a covalent bond with the receptor, whereas chimeras ␦/1, /␦3, and /␦4 do not. When [ Although SUPERFIT is a ␦ selective irreversible ligand, its parent compound, cis-(ϩ)-3-methylfentanyl is a selective agonist (27). Similarly, fentanyl is a selective agonist for the receptor (28), yet its isothiocyanate derivative, FIT, is a selective irreversible ligand for the ␦ receptor (29).…”

Section: Resultsmentioning

confidence: 99%

Irreversible Binding of cis-(+)-3-Methylfentanyl Isothiocyanate to the δ Opioid Receptor and Determination of Its Binding Domain

Zhu

Yin

Law

et al. 1996

Journal of Biological Chemistry

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Binding of cis-(؉)-Opiate and opioid drugs, acting on membrane-bound receptors, have been widely used as analgesics. They, however, also produce side effects such as respiratory depression, decreased gastrointestinal motility, sedation, and mood changes (1). At least three types (, ␦, and ) of opioid receptor are present in the nervous system (1). Many structurally diverse opiates and opioid compounds have been synthesized aiming to minimize the side effects and to understand the structure-function relationship. Some drugs act nonselectively on all three types of opioid receptors, yet there are ligands selective for each receptor.Among the agents synthesized are affinity ligands or irreversible ligands. An affinity ligand is thought to bind to the receptor and then form a covalent bond on or near the binding site, resulting in irreversible attachment (2, 3). Affinity ligands have been very useful in the purification of receptors such as the ␦ opioid receptor (4) and in the elucidation of receptor structure. Specific incorporation of radiolabeled affinity ligand into the receptor followed by polyacrylamide gel electrophoresis and fluorography or autoradiography has been used to identify the receptor, to determine molecular mass of the receptor without purification, and to examine the nature of carbohydrate moieties (for example, see Refs. 5 and 6). Because of the covalent nature of the bond between the ligand and the receptor, the site of incorporation, thus part of the binding domain, can be precisely determined by peptide mapping and/or determination of amino acid sequences of labeled fragments (for example, see Ref. 7).SUPERFIT, 1 an isothiocyanate derivative of cis-(ϩ)-3-methylfentanyl (Fig. 1), was synthesized by Burke et al. (8) and found to bind irreversibly to the ␦ receptor. Incubation of NG108-15 cell membranes with SUPERFIT (1-5 nM) followed by extensive washing reduced ␦ binding by 60 -90%. The reduction in ␦ binding was due to a decrease in B max with no change in K d (8). Similar preincubation of rat brain membranes with SUPERFIT (1-5 nM) greatly reduced ␦ receptor binding, without affecting receptor binding. The (ϩ)-enantiomer (SU-PERFIT) was 50 times more potent than its (Ϫ)-enantiomer (9). The high affinity and enantioselectivity of SUPERFIT indicate that the irreversible binding is the result of selective interaction with the ␦ receptor. ␦ opioid receptors have been cloned from several species (10 -16). In addition, and opioid receptors have been cloned (Refs. 17 and 18 and references therein). All three opioid receptors contain seven putative transmembrane helices (TMHs), a common structural motif of a G protein-coupled receptor superfamily. Sequence comparison among the three types of opioid receptors shows substantial divergence in the N-and C-terminal domains as well as extracellular loops, while sequences within TMHs and intracellular loops are very similar. These divergent sequences may contribute to the binding of type-selective ligands.

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Section: Resultsmentioning

confidence: 99%

Irreversible Binding of cis-(+)-3-Methylfentanyl Isothiocyanate to the δ Opioid Receptor and Determination of Its Binding Domain

Zhu

Yin

Law

et al. 1996

Journal of Biological Chemistry

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“…These compounds had high potential for abuse, because of their ease of synthesis and high analgesic activity. The structures of fentanyl (1) and 11 synthesized analogues (2-12) examined in this study are shown in Tables 1-4. Although there are a number of reports regarding the analgesic activities of some of these analogues [8][9][10][11][12][13][14][15], there have been only a few reports on the actually abused analogues [8]; there have been no reports on α-methylfentanyl (2), the most widely abused analogue. Furthermore, comparison of their analgesic activities with those of morphine and fentanyl was not described.…”

Section: Introductionmentioning

confidence: 99%

Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues

2008

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“…TMF has so far been involved only in relatively short-lived epidemics [3,4]. This is obviously due to the high potency of this opioid drug and the associated dosing problems: the cis-(+)-isomer of TMF is approximately 7,000 times as potent as morphine while the trans-(±)-isomer is approximately 1,000 times as potent [5]. Figure 1 shows the chemical structures of fentanyl, alpha-methylfentanyl, and cis-and trans-TMF.…”

Section: Introductionmentioning

confidence: 99%

An epidemic of fatal 3-methylfentanyl poisoning in Estonia

Ojanperä

Gergov

Liiv³

et al. 2008

Int J Legal Med

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An exceptional epidemic of poisonings due to the highly potent opioid designer drug 3-methylfentanyl (TMF) was revealed among Estonian drug users in 2005-2006 by post-mortem forensic toxicology. Quantitative analysis of cis-TMF, trans-TMF, and fentanyl was performed by liquid chromatography-tandem mass spectrometry. Comprehensive toxicological analysis was performed using a multi-technique approach. The number of TMF-related fatal accidental poisonings identified was 46 and 71 for 2005 and 2006, respectively. The proportion of male victims was 91.5% and the mean age of all victims was 26 years at death. TMF was used predominantly by intravenous injection. There was no significant difference in the blood concentrations of cis-TMF and trans-TMF between pure TMF poisonings and mixed TMF poisonings. The mean combined concentration of TMF stereoisomers among pure TMF cases (1.9 microg/l) was more than ten times lower than the mean fentanyl concentration in fentanyl-related fatalities. Concomitant use of other drugs involved alcohol, amphetamines, benzodiazepines, and cannabis, but very rarely other opioids.

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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

Cited by 150 publications

References 5 publications

Irreversible Binding of cis-(+)-3-Methylfentanyl Isothiocyanate to the δ Opioid Receptor and Determination of Its Binding Domain

Irreversible Binding of cis-(+)-3-Methylfentanyl Isothiocyanate to the δ Opioid Receptor and Determination of Its Binding Domain

Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues

An epidemic of fatal 3-methylfentanyl poisoning in Estonia

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