Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues

Bańkowski, Krzysztof; Witkowska, Ewa; Michalak, Olga; Sidoryk, Katarzyna; Szymanek, Ewa; Antkowiak, Bożena; Paluch, Małgorzata; Filip, Katarzyna; Cebrat, Marek; Setner, Bartosz; Szewczuk, Zbigniew; Stefanowicz, Piotr; Cmoch, Piotr; Izdebski, Jan

doi:10.1016/j.ejmech.2013.02.019

Cited by 9 publications

(7 citation statements)

References 24 publications

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“…It is worth mentioning that u KTP‐NH 2 also had a more enduring analgesic effect than KTP‐NH 2 . Therefore, the substitution of a peptide bond by a urea bond probably succeeded in conferring resistance to peptidases relative to KTP‐NH 2 without complete loss of analgesic power.…”

Section: Discussionmentioning

confidence: 99%

Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

et al. 2015

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Amidated kyotorphin (L-Tyr-L-Arg-NH2; KTP-NH2) causes analgesia when systemically administered. The lipophilic ibuprofen-conjugated derivative of KTP-NH2 has improved analgesic efficacy. However, fast degradation by peptidases impacts negatively in the pharmacodynamics of these drugs. In this work, selected derivatives of KTP and KTP-NH2 were synthesized to combine lipophilicity and resistance to enzymatic degradation. Eight novel structural modifications were tested for the potential to transverse lipid membranes and to evaluate their efficacy in vivo. The rationale behind the design of the pool of the eight selected molecules consisted in the addition of individual group at the N-terminus, namely the tert-butyloxycarbonyl (Boc), γ-aminobutyric acid (GABA), acetyl, butanoyl, and propanoyl or in the substitution of the tyrosine residue by an indole moiety and in the replacement of the peptidic bond by a urea-like bond in some cases. All the drugs used in the study are intrinsically fluorescent, which enables the use of spectrofluorimetry to sample the drugs in the permeation assays. The results show that the BOC and indolyl derivatives of KTP-NH2 have maximal ability to permeate membranes with concomitant maximal analgesic power. Overall, the results demonstrate that membrane permeation is correlated with analgesic efficacy. However, this is not the only factor accounting for analgesia. KTP-NH2 for instance has low passive permeation but is known to have central action. In this case, hypothetical transcytosis over the blood-brain barrier seems to depend on dipeptide transporters.

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Section: Discussionmentioning

confidence: 99%

Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

et al. 2015

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“…One of the analogues, namely the N ε ,N β ‐carbonyl‐D‐Lys 2 ,Dap 5 ]enkephalinamide (or {[Tyr‐D‐Lys(& 1 )‐Gly‐Phe‐Dap(& 2 )‐NH 2 ][& 1 CO& 2 ]} according to the abbreviated nomenclature, ) is an analogue which also showed a strong and long‐lasting antinociception effect in both hot‐plate and tail‐immersion tests for rats after central administration . Recently, while continuing this study, we reported a novel series of tetrapeptide N ‐ureidoethylamides based on the deltorphin(1–4) structure . The antinociceptive activities of these analogues were evaluated using hot‐plate and tail‐flick tests after intravenous application.…”

Section: Introductionmentioning

confidence: 73%

“…The most active analogue {[Tyr‐D‐Lys(& 1 )‐Phe‐Dab(& 2 )‐CH 2 CH 2 NH‐CONH 2 ] [& 1 CO& 2 ]} 1 showed a significant antinociceptive effect after systemic application, stronger than morphine. Moreover, all peptides described in this study were completely resistant toward proteolytic enzymes, likely due to the presence of D‐amino acid residue in position 2 of the peptide chain and the rigid cyclic structure with carbonyl bridge.…”

Section: Introductionmentioning

confidence: 91%

N -terminal guanidinylation of the cyclic 1,4-ureido-deltorphin analogues: the synthesis, receptor binding studies, and resistance to proteolytic digestion

et al. 2015

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The synthesis of a series of N-guanidinylated cyclic ureidopeptides, analogues of 1,4-ureido-deltorphin/dermorphine tetrapeptide is described. The δ- and μ-opioid receptor affinity of new guanidinylated analogues and their non-guanidinylated precursors was determined by the displacement radioligand binding experiments. Our results indicate that the guanidinylation of cyclic 1,4-ureidodeltorphin peptide analogues does not exhibit a uniform influence on the opioid receptor binding properties, similarly as reported earlier for some linear peptides. All analogues were also tested for their in vitro resistance to proteolysis during incubation with large excess of chymotrypsin, pepsin, and papain by means of mass spectroscopy. Guanidinylated ureidopeptides 1G-4G showed mixed μ agonist/δ agonist properties and high enzymatic stability indicating their potential as therapeutic agents for treatment of pain.

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“…Because pain relief is mediated mainly through MOR, it is important to understand the interactions between MOR ligands and the receptor. Therefore, hundreds of analogues of the dermorphin and dermorphin‐like peptides have been synthesised .…”

Section: Introductionmentioning

confidence: 99%

The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

Maciejczyk

Lasota

Frączak

et al. 2016

Journal of Peptide Science

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The synthesis of new dermorphin analogues is described. The (R)-alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α-methyl-β-azidoalanine or α-benzyl-β-azido(1-piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [(3) H]DAMGO (a μ ligand) and [(3) H]DELT (a δ ligand). The most active analogue in this series, Tyr-(R)-Ala-(R)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 and its epimer were analysed by (1) H and (13) C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around C(α) in the α-benzyl-β-azidoAla residue in position 3. The (R) configuration led to the formation of a type I β-turn, whilst switching to the (S) configuration gave rise to an inverse β-turn of type I', followed by the formation of a very short β-sheet. The selectivity of Tyr-(R)-Ala-(R) and (S)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues

Cited by 9 publications

References 24 publications

Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

N -terminal guanidinylation of the cyclic 1,4-ureido-deltorphin analogues: the synthesis, receptor binding studies, and resistance to proteolytic digestion

The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

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