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Developmental Potential for Endomorphin Opioidmimetic Drugs
Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unac...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411882/ https://www.ncbi.nlm.nih.gov/pubmed/25954530 http://dx.doi.org/10.1155/2012/715123 |
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author | Okada, Yoshio Tsuda, Yuko Salvadori, Severo Lazarus, Lawrence H. |
author_facet | Okada, Yoshio Tsuda, Yuko Salvadori, Severo Lazarus, Lawrence H. |
author_sort | Okada, Yoshio |
collection | PubMed |
description | Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr(1) with 2′,6′-dimethyl-l-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt(1)]EM-1 and [Dmt(1)]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt(1)]EM-1 (47) and [N-allyl-Dmt(1)]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier. |
format | Online Article Text |
id | pubmed-4411882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-44118822015-05-07 Developmental Potential for Endomorphin Opioidmimetic Drugs Okada, Yoshio Tsuda, Yuko Salvadori, Severo Lazarus, Lawrence H. Int J Med Chem Review Article Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr(1) with 2′,6′-dimethyl-l-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt(1)]EM-1 and [Dmt(1)]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt(1)]EM-1 (47) and [N-allyl-Dmt(1)]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier. Hindawi Publishing Corporation 2012 2012-06-15 /pmc/articles/PMC4411882/ /pubmed/25954530 http://dx.doi.org/10.1155/2012/715123 Text en Copyright © 2012 Yoshio Okada et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Article Okada, Yoshio Tsuda, Yuko Salvadori, Severo Lazarus, Lawrence H. Developmental Potential for Endomorphin Opioidmimetic Drugs |
title | Developmental Potential for Endomorphin Opioidmimetic Drugs |
title_full | Developmental Potential for Endomorphin Opioidmimetic Drugs |
title_fullStr | Developmental Potential for Endomorphin Opioidmimetic Drugs |
title_full_unstemmed | Developmental Potential for Endomorphin Opioidmimetic Drugs |
title_short | Developmental Potential for Endomorphin Opioidmimetic Drugs |
title_sort | developmental potential for endomorphin opioidmimetic drugs |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411882/ https://www.ncbi.nlm.nih.gov/pubmed/25954530 http://dx.doi.org/10.1155/2012/715123 |
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