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Anna Janecka - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis, biological evaluation and structural analysis of novel peripherally active Morphiceptin analogs
    Bioorganic & medicinal chemistry, 2016
    Co-Authors: Anna Adamska, Anna Janecka, Alicja Kluczyk, Maria Camilla Cerlesi, Girolamo Calo, Attila Borics
    Abstract:

    Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a tetrapeptide amide, is a selective ligand of the μ-opioid receptor (MOR). This study reports the synthesis and biological evaluation of a series of novel Morphiceptin analogs modified in positions 2 or/and 4 by introduction of 4,4-difluoroproline (F2Pro) in l or d configuration. Depending on the fluorinated amino acid configuration and its position in the sequence, new analogs behaved as selective full MOR agonists showing high, moderate, or relatively low potency. The most potent analog, Tyr-F2Pro-Phe-D-F2Pro-NH2, was also able to activate the κ-opioid receptor (KOR), although with low potency. Docking studies and the comparison of results with the high resolution crystallographic structure of a MOR-agonist complex revealed possible structure-activity relationships of this compound family.

  • Functional characterization of opioid receptor ligands by aequorin luminescence-based calcium assay4399
    'American Society for Pharmacology & Experimental Therapeutics (ASPET)', 2006
    Co-Authors: Jakub Fichna, K. Gach, M. Piestrzeniewicz, E. Burgeon, J. Poels, V. Broeck, Anna Janecka
    Abstract:

    A functional assay, based on aequorin-derived luminescence triggered by receptor-mediated changes in intracellular calcium levels, was used to examine relative potency and efficacy of the mu-opioid agonists endomorphin-1, endomorphin-2, Morphiceptin, and their position 3-substituted analogs, as well as the delta-agonist deltorphin-II. The results of the aequorin assay, performed on recombinant cell lines, were compared with those obtained in the functional assay on isolated tissue preparations (guinea pig ileum and mouse vas deferens). A range of nine opioid peptide ligands produced a similar rank order of potency for the mu- and delta-opioid receptor agonists in both functional assays. The highest potency at the mu-receptor was observed for endomorphin-1, endomorphin-2, and [D-1-Nal3]Morphiceptin, whereas deltorphin-II was the most potent delta-receptor agonist. In the aequorin assay, the mu- and delta-agonist-triggered luminescence was inhibited by the opioid antagonists naloxone and naltrindole, respectively. We can conclude that the use of the aequorin assay for new mu- and delta-receptor-selective opioid analogs gives pharmacologically relevant data and allows high-throughput compound screening, which does not involve radioactivity or animal tissues. This is the first study that validates the application of this assay in the screening of opioid analogs

  • synthesis and antinociceptive activity of cyclic endomorphin 2 and Morphiceptin analogs
    Biochemical Pharmacology, 2005
    Co-Authors: Anna Janecka, Jakub Fichna, Jean Costentin, Rafal Kruszynski, Yusuke Sasaki, Akihiro Ambo, Jeanclaude Dorego
    Abstract:

    Abstract Cyclic analogs of the opioid peptides endomorphin-2 and Morphiceptin of the type Tyr-X-Phe-Phe-Y-NH 2 and Tyr-X-Phe- d -Pro-Y-NH 2 (X = Lys or Asp and Y = Lys or Asp), respectively, were synthesized in order to test their structure–activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp 2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective κ antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the μ-opioid receptor and no affinity at δ- and κ-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the κ-opioid receptor.

  • Characterization of antinociceptive activity of novel endomorphin-2 and Morphiceptin analogs modified in the third position.
    Biochemical pharmacology, 2005
    Co-Authors: Jakub Fichna, Jean Costentin, Jean-claude Do Rego, Piotr Kosson, Anna Janecka
    Abstract:

    Abstract In the present study we investigated and compared the in vivo analgesia of centrally administered endomorphin-2 and Morphiceptin, and their analogs modified in position 3. Two series of analogs were synthesized by introducing unnatural aromatic amino acids in the d configuration: 3-(1-naphthyl)- d -alanine ( d -1-Nal), 3-(2-naphthyl)- d -alanine ( d -2-Nal), 3-(4-chlorophenyl)- d -alanine ( d -ClPhe), 3-(3,4-dichlorophenyl)- d -alanine ( d -Cl 2 Phe). Antinociceptive activity of endomorphin-2, Morphiceptin, and their analogs was compared in the mouse hot-plate test, performed after i.c.v. administration of the peptides at a dose of 10 μg/animal. The best results were obtained for two Morphiceptin analogs, [ d -Phe 3 ]Morphiceptin and [ d -1-Nal 3 ]Morphiceptin, which showed greatly improved analgesic activity, as compared to Morphiceptin. In the endomorphin-2 series none of the modifications produced analogs more potent than the parent compound, but [ d -1-Nal 3 ]endomorphin-2 was the best analog. Antinociception induced by endomorphin-2 was reversed by concomitant i.c.v. administration of [ d -Phe 3 ]endomorphin-2, [ d -2-Nal 3 ]endomorphin-2, and [ d -2-Nal 3 ]Morphiceptin, indicating that these analogs were weak μ-opioid antagonists.

  • effect of cerebral ventricles perfusion with Morphiceptin and met enkephalin on trigemino hypoglossal reflex in rats
    Journal of Physiology and Pharmacology, 2002
    Co-Authors: Maria Zubrzycka, Jakub Fichna, Anna Janecka
    Abstract:

    Opioids administered by intracerebroventricular injections produce analgesic responses in rats. The present study was undertaken to investigate the effects of a highly selective mu-opioid receptor ligand Morphiceptin on trigemino-hypoglossal reflex in rats. The analgesic effect of Morphiceptin was compared with another opioid peptide, Met-enkephalin. With the experimental settings used in this study, we have demonstrated that both Morphiceptin and Met-enkephalin show significant dose-dependent analgesic effects after i.c.v. administration in rats as assayed by trigemino-hypoglossal reflex test. The antinociceptive response to Met-enkephalin was short lasting and was observed 10 to 15 min after i.c.v. perfusion. Morphiceptin had a relatively longer duration of antinociceptive action, the effect was observed 20-50 min after i.c.v. perfusion. Neither Morphiceptin nor Met-enkephalin produced antinociception after peripheral injections. The results of the present study indicate that both tested peptides act at mu-opioid receptors situated in the central nervous system. They also suggest that mu-opioid receptors present in the central nervous system are an important element of the trigemino-hypoglossal reflex arc. For that reason selective mu-opioid receptor ligands, like Morphiceptin, inhibit the reflex more significantly.

Jakub Fichna - One of the best experts on this subject based on the ideXlab platform.

  • effect of 2 6 dimethyl l tyrosine dmt on pharmacological activity of cyclic endomorphin 2 and Morphiceptin analogs
    Bioorganic & Medicinal Chemistry, 2011
    Co-Authors: Jakub Fichna, Géza Tóth, Alicja Kluczyk, K. Gach, Jeanclaude Dorego, Renata Perlikowska, Anna Wyrebska, Justyna Piekielna, Tomasz Janecki
    Abstract:

    Abstract This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and Morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa)NH 2 or Tyr-c(Xaa-Phe- d -Pro-Yaa)NH 2 , respectively, where Xaa and Yaa were l / d Asp or l / d Lys. Further modification of these analogs was achieved by introduction of 2′,6′-dimethyl- l -tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure. Dmt 1 -substituted analogs displayed high affinity at the μ-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting μ-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration. Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood–brain barrier permeability.

  • Functional characterization of opioid receptor ligands by aequorin luminescence-based calcium assay4399
    'American Society for Pharmacology & Experimental Therapeutics (ASPET)', 2006
    Co-Authors: Jakub Fichna, K. Gach, M. Piestrzeniewicz, E. Burgeon, J. Poels, V. Broeck, Anna Janecka
    Abstract:

    A functional assay, based on aequorin-derived luminescence triggered by receptor-mediated changes in intracellular calcium levels, was used to examine relative potency and efficacy of the mu-opioid agonists endomorphin-1, endomorphin-2, Morphiceptin, and their position 3-substituted analogs, as well as the delta-agonist deltorphin-II. The results of the aequorin assay, performed on recombinant cell lines, were compared with those obtained in the functional assay on isolated tissue preparations (guinea pig ileum and mouse vas deferens). A range of nine opioid peptide ligands produced a similar rank order of potency for the mu- and delta-opioid receptor agonists in both functional assays. The highest potency at the mu-receptor was observed for endomorphin-1, endomorphin-2, and [D-1-Nal3]Morphiceptin, whereas deltorphin-II was the most potent delta-receptor agonist. In the aequorin assay, the mu- and delta-agonist-triggered luminescence was inhibited by the opioid antagonists naloxone and naltrindole, respectively. We can conclude that the use of the aequorin assay for new mu- and delta-receptor-selective opioid analogs gives pharmacologically relevant data and allows high-throughput compound screening, which does not involve radioactivity or animal tissues. This is the first study that validates the application of this assay in the screening of opioid analogs

  • synthesis and antinociceptive activity of cyclic endomorphin 2 and Morphiceptin analogs
    Biochemical Pharmacology, 2005
    Co-Authors: Anna Janecka, Jakub Fichna, Jean Costentin, Rafal Kruszynski, Yusuke Sasaki, Akihiro Ambo, Jeanclaude Dorego
    Abstract:

    Abstract Cyclic analogs of the opioid peptides endomorphin-2 and Morphiceptin of the type Tyr-X-Phe-Phe-Y-NH 2 and Tyr-X-Phe- d -Pro-Y-NH 2 (X = Lys or Asp and Y = Lys or Asp), respectively, were synthesized in order to test their structure–activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp 2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective κ antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the μ-opioid receptor and no affinity at δ- and κ-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the κ-opioid receptor.

  • Characterization of antinociceptive activity of novel endomorphin-2 and Morphiceptin analogs modified in the third position.
    Biochemical pharmacology, 2005
    Co-Authors: Jakub Fichna, Jean Costentin, Jean-claude Do Rego, Piotr Kosson, Anna Janecka
    Abstract:

    Abstract In the present study we investigated and compared the in vivo analgesia of centrally administered endomorphin-2 and Morphiceptin, and their analogs modified in position 3. Two series of analogs were synthesized by introducing unnatural aromatic amino acids in the d configuration: 3-(1-naphthyl)- d -alanine ( d -1-Nal), 3-(2-naphthyl)- d -alanine ( d -2-Nal), 3-(4-chlorophenyl)- d -alanine ( d -ClPhe), 3-(3,4-dichlorophenyl)- d -alanine ( d -Cl 2 Phe). Antinociceptive activity of endomorphin-2, Morphiceptin, and their analogs was compared in the mouse hot-plate test, performed after i.c.v. administration of the peptides at a dose of 10 μg/animal. The best results were obtained for two Morphiceptin analogs, [ d -Phe 3 ]Morphiceptin and [ d -1-Nal 3 ]Morphiceptin, which showed greatly improved analgesic activity, as compared to Morphiceptin. In the endomorphin-2 series none of the modifications produced analogs more potent than the parent compound, but [ d -1-Nal 3 ]endomorphin-2 was the best analog. Antinociception induced by endomorphin-2 was reversed by concomitant i.c.v. administration of [ d -Phe 3 ]endomorphin-2, [ d -2-Nal 3 ]endomorphin-2, and [ d -2-Nal 3 ]Morphiceptin, indicating that these analogs were weak μ-opioid antagonists.

  • effect of cerebral ventricles perfusion with Morphiceptin and met enkephalin on trigemino hypoglossal reflex in rats
    Journal of Physiology and Pharmacology, 2002
    Co-Authors: Maria Zubrzycka, Jakub Fichna, Anna Janecka
    Abstract:

    Opioids administered by intracerebroventricular injections produce analgesic responses in rats. The present study was undertaken to investigate the effects of a highly selective mu-opioid receptor ligand Morphiceptin on trigemino-hypoglossal reflex in rats. The analgesic effect of Morphiceptin was compared with another opioid peptide, Met-enkephalin. With the experimental settings used in this study, we have demonstrated that both Morphiceptin and Met-enkephalin show significant dose-dependent analgesic effects after i.c.v. administration in rats as assayed by trigemino-hypoglossal reflex test. The antinociceptive response to Met-enkephalin was short lasting and was observed 10 to 15 min after i.c.v. perfusion. Morphiceptin had a relatively longer duration of antinociceptive action, the effect was observed 20-50 min after i.c.v. perfusion. Neither Morphiceptin nor Met-enkephalin produced antinociception after peripheral injections. The results of the present study indicate that both tested peptides act at mu-opioid receptors situated in the central nervous system. They also suggest that mu-opioid receptors present in the central nervous system are an important element of the trigemino-hypoglossal reflex arc. For that reason selective mu-opioid receptor ligands, like Morphiceptin, inhibit the reflex more significantly.

Jeanclaude Dorego - One of the best experts on this subject based on the ideXlab platform.

  • effect of 2 6 dimethyl l tyrosine dmt on pharmacological activity of cyclic endomorphin 2 and Morphiceptin analogs
    Bioorganic & Medicinal Chemistry, 2011
    Co-Authors: Jakub Fichna, Géza Tóth, Alicja Kluczyk, K. Gach, Jeanclaude Dorego, Renata Perlikowska, Anna Wyrebska, Justyna Piekielna, Tomasz Janecki
    Abstract:

    Abstract This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and Morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa)NH 2 or Tyr-c(Xaa-Phe- d -Pro-Yaa)NH 2 , respectively, where Xaa and Yaa were l / d Asp or l / d Lys. Further modification of these analogs was achieved by introduction of 2′,6′-dimethyl- l -tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure. Dmt 1 -substituted analogs displayed high affinity at the μ-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting μ-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration. Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood–brain barrier permeability.

  • synthesis and antinociceptive activity of cyclic endomorphin 2 and Morphiceptin analogs
    Biochemical Pharmacology, 2005
    Co-Authors: Anna Janecka, Jakub Fichna, Jean Costentin, Rafal Kruszynski, Yusuke Sasaki, Akihiro Ambo, Jeanclaude Dorego
    Abstract:

    Abstract Cyclic analogs of the opioid peptides endomorphin-2 and Morphiceptin of the type Tyr-X-Phe-Phe-Y-NH 2 and Tyr-X-Phe- d -Pro-Y-NH 2 (X = Lys or Asp and Y = Lys or Asp), respectively, were synthesized in order to test their structure–activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp 2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective κ antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the μ-opioid receptor and no affinity at δ- and κ-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the κ-opioid receptor.

Peg Davis - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and activity of endomorphin 2 and Morphiceptin analogues with proline surrogates in position 2
    European Journal of Medicinal Chemistry, 2010
    Co-Authors: Cesare Giordano, Adriano Mollica, Francesco Pinnen, Federica Feliciani, Gino Lucente, Anna Sansone, Annalisa Masi, Pasqualina Punzi, Ivana Cacciatore, Peg Davis
    Abstract:

    The opioid agonists endomorphins (Tyr-Pro-Trp-Phe-NH(2); EM1 and Tyr-Pro-Phe-Phe-NH(2); EM2) and Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) exhibit an extremely high selectivity for mu-opioid receptor. Here a series of novel EM2 and Morphiceptin analogues containing in place of the proline at position 2 the S and R residues of beta-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (betaPrs) have been synthesized and their binding affinity and functional activity have been investigated. The highest micro-receptor affinity is shown by [(S)betaPrs(2)]EM2 analogue (6e) which represents the first example of a beta-sulphonamido analogue in the field of opioid peptides.

  • Synthesis and activity of endomorphin-2 and Morphiceptin analogues with proline surrogates in position 2
    'Elsevier BV', 2010
    Co-Authors: Cesare Giordano, Adriano Mollica, Francesco Pinnen, Federica Feliciani, Gino Lucente, Anna Sansone, Annalisa Masi, Pasqualina Punzi, Ivana Cacciatore, Peg Davis
    Abstract:

    The opioid agonists endomorphins (Tyr-Pro-Trp-Phe-NH(2); EM1 and Tyr-Pro-Phe-Phe-NH(2); EM2) and Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) exhibit an extremely high selectivity for mu-opioid receptor. Here a series of novel EM2 and Morphiceptin analogues containing in place of the proline at position 2 the S and R residues of beta-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (beta Prs) have been synthesized and their binding affinity and functional activity have been investigated. The highest p-receptor affinity is shown by [(S)beta Prs(2)]EM2 analogue (6e) which represents the first example of a beta-sulphonamido analogue in the field of mold peptides. (C) 2010 Elsevier Masson SAS. All rights reserved

  • Morphiceptin and β casomorphin 5 analogues containing a reduced peptide bond selective μ receptor agonists and a novel μ antagonist h tyr proψ ch2 nh phe pro gly oh
    Biopolymers, 1992
    Co-Authors: Nancy G J Delaet, Peg Davis, Patricia Verheyden, Dirk Tourwe, G Van Binst, Thomas F. Burks
    Abstract:

    : In order to prevent enzymatic degradation of beta-casomorphin-5 (1) and Morphiceptin, reduced peptide bonds were incorporated at the 2-3 and 3-4 bonds, respectively. The analogues were synthesized by a combination of solid phase methodology and reductive alkylation of resin-bound peptide amines with Boc-amino acid aldehydes (Boc: tert-butyloxycarbonyl) in the presence of NaBH3CN. During reversed phase high pressure liquid chromatography purification, peak shape distortions could be observed. Epimerization was excluded, based on gas chromatography/mass spectroscopy analysis, which indicated acceptable levels of racemization (less than 3%) in the crude product. Instead, the phenomena could be attributed to slow cis/trans isomerizations originating from the Xxx-Pro bonds in the sequence. The presence of different conformational isomers was also established by 1H-nmr spectroscopy in DMSO-d6. All analogues showed high stability in blood plasma, enhanced binding affinity for the mu receptor, and very low binding to the delta receptor. While the Phe 3 psi(CH2-N)Pro4 analogues (3) and (5) displayed agonist activity, the Pro 2 psi(CH2-NH)Phe3 modified analogue (2) showed antagonist activity comparable to D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2.

Robert L Macdonald - One of the best experts on this subject based on the ideXlab platform.

  • Dynorphin and neoendorphin peptides decrease dorsal root ganglion neuron calcium-dependent action potential duration
    2016
    Co-Authors: M A Werz, Robert L Macdonald
    Abstract:

    Opioid peptides decrease somatic calcium-dependent action po-tential duration of a subpopulation of mouse dorsal root ganglion (DRG) neurons grown in dissociated cell culture. Based on rank order of potency and naloxone sensitivity, both mu and delta oploid receptors were demonstrated on the somata of DRG neurons and were shown to have a heterogeneous distribution. The purpose of the present investigation was to determine the actions of dynorphin gene products, dynorphin A, dynorphin B, dynorphin A(1-8), dynorphin A(1-9), a-neoendorphin and $-neoendorphin on DRG neuron somatic calcium-dependent action potentials and to compare the actions of dynorphin and neoen-dorphin peptides to the action of Morphiceptin, a mu receptor-selective ligand, and Leu-enkephalin, a delta receptor-preferring ligand. We report that the dynorphin and neoendorphin peptide