- Synthesis and biological evaluation of an orally active glycosylated endomorphin-1
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The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED50 of 8.3 (±0.8) μmol/kg. The corresponding ED50 for morphine was 2.6 (±1.4) ±mol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED 50 = 19.6 (±1.2) ±mol/kg), which was comparable with that of morphine (ED50 = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.
- Varamini, Pegah,Mansfeld, Friederike M.,Blanchfield, Joanne T.,Wyse, Bruce D.,Smith, Maree T.,Toth, Istvan
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- Design, synthesis, and biological activity of new endomorphin analogs with multi-site modifications
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Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the u
- Cui, Jiaming,Han, Chao-zhen-yi,Liu, Xin,Luo, Keyao,Ma, Mengtao,Wang, Jing,Wang, Rui,Wang, Yuan,Wang, Zhaojuan,Yang, Dongxu,Zhang, Xianghui,Zhao, Long,Zhou, Jingjing
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- Modulation of the Interaction between a Peptide Ligand and a G Protein-Coupled Receptor by Halogen Atoms
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Systematic halogenation of two native opioid peptides has shown that halogen atoms can modulate peptide-receptor interactions in different manners. First, halogens may produce a steric hindrance that reduces the binding of the peptide to the receptor. Second, chlorine, bromine, or iodine may improve peptide binding if their positive σ-hole forms a halogen bond interaction with negatively charged atoms of the protein. Lastly, the negative electrostatic potential of fluorine can interact with positively charged atoms of the protein to improve peptide binding.
- Rosa, Mònica,Caltabiano, Gianluigi,Barreto-Valer, Katy,Gonzalez-Nunez, Verónica,Gómez-Tamayo, José C.,Ardá, Ana,Jiménez-Barbero, Jesús,Pardo, Leonardo,Rodríguez, Raquel E.,Arsequell, Gemma,Valencia, Gregorio
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supporting information
p. 872 - 876
(2015/08/24)
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- Efficient chemo-enzymatic synthesis of endomorphin-1 using organic solvent stable proteases to green the synthesis of the peptide
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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1), an effective analgesic, was efficiently synthesized by a combination of enzymatic and chemical methods. Peptide Boc-Trp-Phe-NH2 was synthesized with a high yield of 97.1% by the solvent-stab
- Sun, Honglin,He, Bingfang,Xu, Jiaxing,Wu, Bin,Ouyang, Pingkai
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p. 1680 - 1685
(2011/08/07)
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- Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides
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Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH2), an endogenous opioid with high affinity and selectivity for μ-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N- and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2′,6′-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for μ-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-Terminus modification decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt[1]]-Endo-1 is nine times more stable (t1/2 = 43.5 min), >8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater μ-opioid receptor affinity (Kiμ = 0.08 nM).
- Koda, Yasuko,Del Borgo, Mark,Wessling, Susanne T.,Lazarus, Lawrence H.,Okada, Yoshio,Toth, Istvan,Blanchfield, Joanne T.
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p. 6286 - 6296
(2008/12/22)
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- Differential receptor binding characteristics of consecutive phenylalanines in μ-opioid specific peptide ligand endomorphin-2
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Endogenous opioid peptides consist of a conserved amino acid residue of Phe3 and Phe4, although their binding modes for opioid receptors have not been elucidated in detail. Endomorphin-2, which is highly selective and specific for the μ opioid receptor, possesses two Phe residues at the consecutive positions 3 and 4. In order to clarify the role of Phe3 and Phe4 in binding to the μ receptor, we synthesized a series of analogs in which Phe3 and Phe4 were replaced by various amino acids. It was found that the aromaticity of the Phe-β-phenyl groups of Phe3 and Phe4 is a principal determinant of how strongly it binds to the receptor, although better molecular hydrophobicity reinforces the activity. The receptor binding subsites of Phe3 and Phe4 of endomorphin-2 were found to exhibit different structural requirements. The results suggest that [Trp3]endomorphin-2 (native endomorphin-1) and endomorphin-2 bind to different receptor subclasses.
- Honda, Takeshi,Shirasu, Naoto,Isozaki, Kaname,Kawano, Michiaki,Shigehiro, Daiki,Chuman, Yoshiro,Fujita, Tsugumi,Nose, Takeru,Shimohigashi, Yasuyuki
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p. 3883 - 3888
(2008/02/12)
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- Endomorphin-1 analogs with enhanced metabolic stability and systemic analgesic activity: Design, synthesis, and pharmacological characterization
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We synthesized four new analogs of endomorphin-1 by systematic chemical modifications. To identify the best possible drug candidates for clinical pain management and to investigate the potential contribution of these alterations to the biological activity, their pharmacological properties were determined. All of the analogs showed significantly enhanced metabolic stability. The fact that centrally mediated analgesia following peripheral administration was observed with one of the analogs suggested the approach design undertaken here had validity in the development of endomorphin-1 as a successful opioid drug for the clinic.
- Liu, Hongmei,Zhang, Bangzhi,Liu, Xuefeng,Wang, Changlin,Ni, Jingman,Wang, Rui
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p. 1694 - 1702
(2008/02/03)
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- Structure-Activity Study on the Phe Side Chain Arrangement of Endomorphins Using Conformationally Constrained Analogues
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Structure-activity study on the Phe side chain arrangement of endomorphins using conformationally constrained analogues.Endomorphins-1 and -2 were substituted with all the beta-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for beta-MePhe(4)-endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-beta-MePhe(4) resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their micro opioid affinities were 4-times higher than the parent peptides, they stimulated [(35)S]GTPgammaS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-beta-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the chi(1) = -60 degrees rotamer of Phe(4) in the binding conformer of endomorphins. Our results emphasize that the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial for binding to the micro opioid receptor.
- Toemboely, Csaba,Koever, Katalin E.,Peter, Antal,Tourwe, Dirk,Biyashev, Dauren,Benyhe, Sandor,Borsodi, Anna,Al-Kharasani, Mahmoud,Ronai, Andras Z.,Toth, Geza
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p. 735 - 743
(2007/10/03)
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- Synthesis and binding activity of endomorphin-1 analogues β-amino acids
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Endomorphin-1 (Tyr-Pro-Trp-PheNH2) has been proposed as the most potent endogenous ligand of the μ-opioid receptors. In this paper, we describe the synthesis of some endomorphin-1 based tetrapeptides in which a residue of the sequence Tyr-Pro-Trp-PheNH2 is replaced by the corresponding β-isomer. These novel peptides showed different affinities for the opioid receptors labeled with [3H]-DAMGO in rat brain membranes, depending on the β-amino acid. In particular, the tetrapeptide containing β-Pro (Tyr-β-(R)-Pro-Trp-PheNH2) displayed a higher affinity than endogenous endomorphin-1, as revealed by their K(i) values (0.33 and 11.1 nM, respectively). (C) 2000 Elsevier Science Ltd.
- Cardillo, Giuliana,Gentilucci, Luca,Melchiorre, Paolo,Spampinato, Santi
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p. 2755 - 2758
(2007/10/03)
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