Design, Synthesis and Pharmacological Characterization of Endomorphin Analogues with Non‐Cyclic Amino Acid Residues in Position 2

Perlikowska, Renata; Fichna, Jakub; Wyrębska, Anna; Poels, Jeroen; Broeck, Jozef Vanden; Tóth, Géza; Storr, Martin; Rego, Jean–Claude do; Janecka, Anna

doi:10.1111/j.1742-7843.2009.00476.x

Cited by 17 publications

(23 citation statements)

References 32 publications

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“…However, hydrolysis and isolation of the expected products failed. The planned α/β-tetrapeptides (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were then synthesized in solution. First, dipeptides were formed from respective α-or β 2 -Homo amino acid derivatives.…”

Section: Chemistrymentioning

confidence: 99%

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β2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

et al. 2020

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TAPP (H-Tyr-d-Ala-Phe-Phe-NH2) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β2-Homo-amino acid (β2hAA) scan of the TAPP sequence. To this aim, 10 novel analogues have been synthesized and evaluated for µ-opioid and δ-opioid receptor affinity as well as for stability in human plasma. The derivatives included compounds in which a (R)- or (S)-β2-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-β2hPhe4 turned out to bind µOR with affinities equal to that of the parent. β2hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β2-Homologation in the second position gave derivatives with very poor µOR binding. According to molecular modelling, the presented α/β-peptides adopt a variety of binding poses with their common element being an ionic interaction between a protonable amine of the first residue and Asp147. A feature required for high µOR affinity seems the ability to accommodate the ring in the fourth residue in a manner similar to that found for TAPP. Contrary to what might be expected, several compounds were significantly less stable in human plasma than the parent compound.

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Section: Chemistrymentioning

confidence: 99%

“…The same paper presented several α/β-hybrides of deltorphin I. Alicyclic β-amino acids as proline mimics were used for studying conformational requirements in endomorphin-1/-2 analogues [7,8]. Other authors replaced proline for β-alanine [9]. Earlier, cyclic β-AAs were applied in studies on morphiceptin [10,11] and dermorphin [12].…”

Section: Introductionmentioning

confidence: 99%

β2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

et al. 2020

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“…All peptide hybrids were synthesized by the standard solid-phase procedure on MBHA Rink-Amide peptide resin using the N α -Fmoc strategy and TBTU as a coupling reagent, according to the method described elsewhere [50]. Final products were purified by RP-HPLC on a Vydac C 18 column (10 µm, 22 × 250 mm) at a flow rate of 2 mL/min, using as an eluent a linear gradient of 0.1% TFA in water (A) and 80% acetonitrile in water containing 0.1% TFA (B) ranging from 0% to 100% B over 25 min.…”

Section: Peptide Synthesismentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Wtorek

Adamska‐Bartłomiejczyk

Piekielna-Ciesielska

et al. 2019

Molecules

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Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.

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“…EM analogues containing D-amino acids also induced effective antinociception in mice assessed in HP or tail-flick (TF) test after i.c.v. administration (21,28). EM analogues containing other natural (e.g.…”

Section: Discussionmentioning

confidence: 99%

Characterization of antinociceptive potency of endomorphin-2 derivatives with unnatural amino acids in rats

Kovács¹,

Petrovszki²,

Mallareddy³

et al. 2012

Acta Physiologica Hungarica

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This study reports on the in vivo effects of four endomorphin-2 (EM-2) derivatives (EMD1-4) containing unnatural amino acids, i.e. 2-aminocyclohexanecarboxylic acid (Achc 2 ), para-fluorophenylalanine (pFPhe 4 ), β-methylphenylalanine (βMePhe 4 ) and/or 2',6'-dimethyltyrosine (Dmt 1 ). After induction of osteoarthritis by monosodium iodoacetate into the ankle joint of male Wistar rats, a chronic intrathecal catheter was inserted for spinal drug delivery. The mechanical threshold was assessed by a dynamic aesthesiometer. Intrathecal injection of the original EM-2 and the ligands (0.3-10 µg) caused dose-dependent antiallodynic effects. The comparison of the different substances revealed that EMD3 and EMD4 showed more prolonged antinociception than EM-2, and the effects of the highest dose of EMD4 were comparable to morphine, while EMD3 caused paralysis at this dose. The potency of the different ligands did not differ from EM-2. The results show that the derivatives of EM-2 have similar in vivo potency to the original ligand, but their effects were more prolonged suggesting that these structural modifications may play a role in the development of novel endomorphin analogues with increased therapeutic potential.Keywords: opioid peptide, endomorphin, pain, spinal, intrathecal, osteoarthritis C Morphine and related compounds that are clinically valuable for pain relief, act primarily at the μ-opioid receptor (MOR), a member of the G-protein-coupled receptor superfamily (39). A major goal in opioid peptide research is the development of novel analgesics that could substitute for morphine without its well-known side effects of dependence, tolerance, respiratory depression and reward-seeking behavior (25). The study of naturally occurring peptides provides a rational and powerful approach in the design of peptide medications. Endomorphin-1 (EM-1, Tyr-Pro-Trp-Phe-NH 2 ) and endomorphin-2 (EM-2, Tyr-Pro-PhePhe-NH 2 ) are high-affinity, MOR-selective endogenous opioids which also inhibit nociception similarly to opiates of plant origin in both acute and chronic pain models (10,31,44). The exogenous application of EMs encounters serious limitations, including a short duration of action, a lack of activity after oral administration and poor metabolic stability (23,34,37). Aminopeptidases play a key role in the biodegradation of EMs, during which the main cleavage occurs at the Pro 2 -Trp 3 and Pro 2 -Phe 3 peptide bonds. For their consideration as actual therapeutic drugs it is essential to enhance their resistance to enzymatic degradation (12).

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Design, Synthesis and Pharmacological Characterization of Endomorphin Analogues with Non‐Cyclic Amino Acid Residues in Position 2

Cited by 17 publications

References 32 publications

β2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

β2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Characterization of antinociceptive potency of endomorphin-2 derivatives with unnatural amino acids in rats

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