Consequences of cis-amide bond simulation in opioid peptides

Olczak, Jacek; Kaczmarek, Krzysztof; Maszczynska, Iwona; Lisowski, Marek; Stropova, Dagmar; Hruby, Victor J.; Yamamura, Henry I.; Lipkowski, Andrzej W.; Zabrocki, Janusz

doi:10.1007/bf02443502

Cited by 3 publications

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References 4 publications

(3 reference statements)

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“…15 All of the other replacements of amides have only been partial. Some replacements involve Nmethyl amides, 24 triazoles and tetrazoles (via click chemistry), 25 sulfonamides, 26 phosphonamidates, 27 ketomethylenes, 28 and retro-inverso amides. 29,30 Because the N-methyl amide and ester functions have the potential to act as hydrogen-bond acceptors and not as hydrogen-bond donors (Figure 1), 14 they can be introduced in peptides to mimic some properties of the amide bond and to study the roles of amide bonds in receptor binding and activity.…”

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Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides

Rochon

Proteau-Gagné

Bourassa

et al. 2013

ACS Chem. Neurosci.

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Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.

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“…All of the other replacements of amides have only been partial. Some replacements involve N -methyl amides, triazoles and tetrazoles (via click chemistry), sulfonamides, phosphonamidates, ketomethylenes, and retro-inverso amides. , …”

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confidence: 99%

Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides

Rochon

Proteau-Gagné

Bourassa

et al. 2013

ACS Chem. Neurosci.

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“…The peptide analogues into which a cis amide bond surrogate has been incorporated are useful for the studies of the active conformation and/or the topology of the active site of original peptides. 1,5-Disubstituted tetrazole is known as a cis amide bond surrogate (Figure ), , and it has been incorporated into bradykinin, CCK-B receptor ligands, somatostatin, leucine-enkephalin, and TRH analogues for their biological activity studies. Tetrazole is a good cis amide bond surrogate.…”

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AcisAmide Bond Surrogate Incorporating 1,2,4-Triazole

et al. 2002

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“…However, the positional scanning of ENKs with a 1,4-disubstituted triazole, 1,5-disubstituted tetrazole, 4-imidazolidinone, and cyclopropane ring was not successful, with an overall loss of activity in most cases. It was suggested that natural amide bonds are critical for receptor interactions, particularly through hydrogen bondings between oxygen and hydrogen atoms [ 275 , 278 , 279 , 280 ]. Another positional scanning of DER-tetrapeptide with piperazin-2-one moieties, N , N ′-ethylene-bridged dipeptides showed slightly different SAR depending on the chirality and backbone [ 281 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.

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Consequences of cis-amide bond simulation in opioid peptides

Cited by 3 publications

References 4 publications

Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides

Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides

AcisAmide Bond Surrogate Incorporating 1,2,4-Triazole

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

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