Synthesis and Biological Activity of Endomorphin‐2 Analogs Incorporating Piperidine‐2‐, 3‐ or 4‐Carboxylic Acids Instead of Proline in Position 2

Staniszewska, Renata; Fichna, Jakub; Gach, Katarzyna; Tóth, Géza; Poels, Jeroen; Broeck, Jozef Vanden; Janecka, Anna

doi:10.1111/j.1747-0285.2008.00678.x

Cited by 24 publications

(20 citation statements)

References 13 publications

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“…In particular, among the recently examined EM-2 analogues containing positional isomers of the 6-membered piperidine-carboxylic acid, replacement of Pro 2 with the chiral nipecotic acid ( viz piperidine-3-carboxylic acid) led, in accordance with the results concerning other related cyclic β-residues,14,15 to a highly active analogue 20. On the contrary, Pro 2 replacement with the achiral piperidine-4-carboxylic acid ( viz isonipecotic acid) resulted, as in the case of the here reported analogue 5 , to a practically inactive ligand 20. It can be argued that the high conformational restriction and the reduced flexibility of the 4-membered achiral 3Aze are detrimental features which prevail over the advantages which, in larger cyclic systems, derive from the presence of a β-positioned carboxylic group.…”

supporting

confidence: 78%

“…Several chemical modifications performed on EMs have been described previously and many of them were focused on the Pro at position 2 12–20. The presence of Pro, the sole proteinogenic amino acid possessing a cyclic structure and a secondary amino group, represents a crucial factor in determining the structural and conformational properties of proteins and peptides.…”

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confidence: 99%

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Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

Torino

Mollica

Pinnen

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-didehydro-(S)-proline (Δ 3 Pro), azetidine-3-carboxylic acid (3Aze) and didehydro-alanine (ΔAla) have been used to prepare [Δ 3 Pro 2 ]EM-2 (1), [Aze 2 ]EM-1 (2), [Aze 2 ]EM-2 (3), [3Aze 2 ]EM-1 (4), [3Aze 2 ]EM-2 (5) and [ΔAla 2 ]EM-2 (6). Binding assays and functional bioactivities for μ-and δ-receptors are reported. The highest affinity, bioactivity and selectivity is shown by peptides 2 and 3 containing the Aze residue.Keywords azetidine carboxylic acids; 3,4-didehydro-(S)-proline; didehydro-alanine; endomorphins; μ-receptors The endogenous neuropeptides endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ; EM-2), originally isolated from bovine brain 1 and subsequently from the human brain cortex, 2 continue to attract considerable attention in the field of opioid peptides. In comparison with the other endogenous peptide ligands of opioid receptors, endomorphins (EMs) combine potency and efficacy with high affinity and selectivity towards the μ-opioid receptor, 1,3,4 the receptor most involved with acute analgesic effects in the central nervous system. 5 Furthermore, the EMs proteolytic stability, although low on a general scale, is the highest among the known endogenous opioid peptides 6,7 and their activity is accompanied by reduced cardiorespiratory side effects, as compared with the reference alkaloid ligand morphine. 8,9 All of these properties, render EMs the object of continuous investigations and a promising target for the development of new opioid analgesics. However, *Corresponding author: Phone 520-621-6332 ; Fax 520-621-8407., E-mail address: hruby@email.arizona.edu (V. J. Hruby). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. as found in the case of most short linear natural peptides, native EMs lack critical therapeutic characteristics such as bioavailability, duration of action and oral activity. 10 Research efforts are then focused on the design of analogues and peptidomimetics in order to improve EMs properties as potential drugs as well as to better understand the key structural and conformational features on which receptor recognition and binding are based. 11 NIH Public AccessSeveral chemical modifications performed on EMs have been described previously and many of them were focused on the Pro at position 2. [12][13][14][15][16][17][18][19][20] The presence of Pro, the sole proteinogenic amino acid possessing a cyclic structure and a s...

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supporting

confidence: 78%

mentioning

confidence: 99%

Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

Torino

Mollica

Pinnen

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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“…An earlier study showed that replacement of Tyr 1 by Dmt resulted in marked increases in receptor-binding affinity and bioactivity in numerous opioid peptide agonists and antagonists (4). Replacement of Pro 2 by alicyclic β-amino acids, pseudoprolines or piperidine-2-, -3-and -4-carboxylic acids resulted in increased affinity for the MOR and enhanced proteolytic stability (7,14,16,35). The insertion of pFPhe in place of the Phe 4 in enkephalin or endomorphins resulted in increased potency in functional assays (22,38).…”

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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“…5), which could serve as a-, b-, and g-amino acids, in position 2, respectively. 40 Configuration of the chiral acids, Pip and Nip, was chosen to be S and R to mimic the spatial arrangement of L-Pro present in EMs (18-20, (Table II), showed similar enhancement of metabolic stability and similar analgesic properties, which were much stronger and longer lasting than those of parent peptide EM-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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Synthesis and Biological Activity of Endomorphin‐2 Analogs Incorporating Piperidine‐2‐, 3‐ or 4‐Carboxylic Acids Instead of Proline in Position 2

Cited by 24 publications

References 13 publications

Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue

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

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