Synthesis and biological evaluation of cyclic endomorphin-2 analogs

Perlikowska, Renata; do-Rego, Jean Claude; Cravezic, Aurore; Fichna, Jakub; Wyrębska, Anna; Tóth, Géza; Janecka, Anna

doi:10.1016/j.peptides.2009.12.002

Cited by 41 publications

(42 citation statements)

References 39 publications

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“…Thus, different cyclic analogues of EM-2 induced more potent and/or prolonged antinociception in the hot-plate (HP) test after i.c.v. administration in mice compared to the parent ligand (17,27,29). EM analogues containing D-amino acids also induced effective antinociception in mice assessed in HP or tail-flick (TF) test after i.c.v.…”

Section: Discussionmentioning

confidence: 99%

“…administration in mice (8,41,43). A number of studies proved that in contrast to the parent ligands, some analogues could produce antinociception after peripheral administration, too, which suggests that these substances can pass thorugh the blood-brain barrier (27). A few studies found that analogues of EMs could antagonise opioid-induced antinociception after i.t.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it was found that the analogues carrying Dmt 1 and Achc 2 residues displayed the highest MOR affinities, depending upon the configuration of the incorporated Achc Combination of such derivatives with pFPhe 4 or βMePhe 4 yielded compounds with high binding potency, while their efficacy did not differ from the parent ligand. Several earlier studies investigated the in vivo activities of different endomorphin derivatives in acute heat or chemical pain models (2,17,24,27,45). The goal of this study was to investigate the antiallodynic effects of the recently synthetized and most potent EM-2 derivatives (EMD1-4, Table I) at spinal level, in a chronic joint pain model.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…51 In addition, the success of cyclic EM analogues, lacking the basic N-terminus cationic amine also indicated that specific, atypical peptide ligands deprived of a cationizable N-terminal amino group could still strongly interact with MOR. [52][53][54][55] What should be kept in mind is that some other positive charge lacking Tyr surrogates, such as (2S)-2-methyl-3-(2…”

Section: A Pro: a Spacer Or An Unusual Visa For Mor Selectivitymentioning

confidence: 99%

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Liu

Wang

2011

Medicinal Research Reviews

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The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

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“…Data indicated that it elicits its effect by stimulating the release of dynorphin A which acts on the κ-opioid receptor [18]. However, the substitution of the amino acid in position 2 by its enantiomer resulted in a potent analgesic with high µ-opioid receptor affinity [19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

Mansfeld¹,

Tóth²

2012

IJOC

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Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the µ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further increase in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma.

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Synthesis and biological evaluation of cyclic endomorphin-2 analogs

Cited by 41 publications

References 39 publications

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

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

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

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