Side Chain Modifications Change the Binding and Agonist Properties of Endomorphin 2

Lengyel, Imre; Orosz, György; Biyashev, Dauren; Kocsis, László; Al-Khrasani, Mahmoud; Rónai, András Z.; Tömböly, Cs.; Fürst, Zsuzsanna; Tóth, Géza; Borsodi, Anna

doi:10.1006/bbrc.2001.6136

Cited by 38 publications

(39 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The concentration of test compound at the beginning of the experiment was 100 μM, and the assay was performed at 37° C shaking at 400 rpm. Samples (10 μL) were taken at selected time points (5,10,15,20,30,40,50,60 and 120 minutes) and immediately added to 5 μL of TFA to stop digestion and then diluted with 85 μL of water/DMSO solution so that there was a final concentration of 10% by volume of DMSO. This addition of DMSO was shown to improve the resolution and reproducibility of the LC/MS analysis, particularly of the lipophilic peptides.…”

Section: Cell Culturementioning

confidence: 99%

“…In this study we have chemically modified the termini of endomorphin 1 to investigate systematically how these changes can affect stability, permeability and biological activity. Structure activity studies on the endomorphins have revealed the importance of the Tyr 1 and Trp 3 residues to receptor binding 15,16 and Pro 2 to the correct structural orientation of the peptide. 17, 18 Our modifications, therefore, concentrated on the addition of lipidic and/or carbohydrate units to either termini while maintaining the native peptide sequence.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Koda

Borgo

Wessling

et al. 2008

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH 2 ), 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 9 times more stable (t ½ = 43.5 min), > 8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater μ-opioid receptor affinity (K iμ = 0.08 nM).

show abstract

Section: Cell Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Koda

Borgo

Wessling

et al. 2008

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…EM1 and EM2 were also characterized for comparison, and the affinity values are in agreement with those published previously (K i (m) = 4.55 and 8.23 nm, respectively). [17,25] The opioid receptor binding properties of the new EM analogues are summarized in (7), which is the most potent EM1 analogue, increased about twofold (K i (m) = 2.32 nm), and d affinity increased 1.6-fold over its parent, consequently giving a slight increase in m selectivity (K i (d)/K i (m) = 1417). Although both m and d affinity of the most potent EM2 derivative 21 increased in binding assays, the selectivity decreased about threefold (K i (d)/K i (m) = 676) relative to that of EM2.…”

Section: Opioid Receptor Affinity and Selectivitymentioning

confidence: 99%

“…It further demonstrates that the distance between the C-terminal aromatic ring and peptide backbone has a strong effect on MOR binding. [25] EM1 and EM2 only differ in one amino acid. The side chain of Trp 3 of EM1 is an indole ring, which is a relatively bulky group compared with Phe 3 of EM2.…”

Section: Solution Conformation Analysismentioning

confidence: 99%

See 1 more Smart Citation

Structure–Activity Study on the Spatial Arrangement of the Third Aromatic Ring of Endomorphins 1 and 2 Using an Atypical Constrained C Terminus

Shao

Cui

et al. 2007

ChemMedChem

View full text Add to dashboard Cite

The discovery of endomorphins (EMs) has opened the possibility of searching for new analgesics. However, the design of peptide analgesics has proven to be very difficult as a result of their conformational flexibility and a lack of clarity in structure-activity relationships (SAR). In EMs, the amino acid side chains exhibit considerable conformational flexibility, especially in the third aromatic ring, which is free to adopt a bioactive conformation. To resolve these problems, a series of C terminus EM analogues, [Xaa(4)-R]EMs, modified through the substitution of Phe(4) with nonaromatic residues and termination with benzyl groups, were designed to generate conformational constrains of the third aromatic ring by amide bond and torsion angles (phi(4) and psi(4)) of Xaa(4). Introduction of (S)-alpha-methyl or (S)/(R)-alpha-carboxamide on the methylene unit of the benzyl group was designed to produce an atypical topographical constraint (phi(5)) of the third aromatic ring rotation. Interestingly, some EM derivatives, with elimination of the C-terminal carboxamide group and significant changes in the address sequence (Phe(4)-NH(2)), still exhibited higher mu-opioid receptor (MOR) affinity than unmodified EMs. In contrast, some analogues with incorrectly constrained C termini displayed very low affinity and pharmacological activities. Thus, our results indicate that these EM analogues, with atypical constrained C termini, provide model compounds with potent MOR agonism. They also give evidence that the proper spatial orientation and conformational restriction of the third aromatic ring are crucial for the interaction of EMs with MOR.

show abstract

Free radical scavenging abilities of flavonyl‐thiazolidine‐2,4‐dione compounds

et al. 2011

View full text Add to dashboard Cite

Free radical scavenging activity of flavonyl-thiazolidine-2,4-dione compounds has been evaluated using chemiluminescence, electron spin resonance spectroscopy with 5,5-dimethyl-1-pyrroline-1-oxide as spin trap and DPPH (2,2'-diphenyl-1-picrylhydrazyl) method. The examined compounds exhibited 28-50% scavenging superoxide anion radical O₂⁻ⁱ16.7-76.7% hydroxyl radical (HO•) and 9-40% DPPH radical. Compounds containing carbonyl group in their structure can be considered as antioxidants with high relevance and great biological importance.

show abstract

Side Chain Modifications Change the Binding and Agonist Properties of Endomorphin 2

Cited by 38 publications

References 38 publications

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Structure–Activity Study on the Spatial Arrangement of the Third Aromatic Ring of Endomorphins 1 and 2 Using an Atypical Constrained C Terminus

Free radical scavenging abilities of flavonyl‐thiazolidine‐2,4‐dione compounds

Contact Info

Product

Resources

About