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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...

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Autores principales: Okada, Yoshio, Tsuda, Yuko, Salvadori, Severo, Lazarus, Lawrence H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2012
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.
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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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