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Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: In Vitro Pharmacology and ADME Profile
[Image: see text] JDTic analogues 4–15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had K(e) = 0.024, 0.01, 0.03...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161151/ https://www.ncbi.nlm.nih.gov/pubmed/25133923 http://dx.doi.org/10.1021/jm5008177 |
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author | Kormos, Chad M. Gichinga, Moses G. Maitra, Rangan Runyon, Scott P. Thomas, James B. Brieaddy, Lawrence E. Mascarella, S. Wayne Navarro, Hernán A. Carroll, F. Ivy |
author_facet | Kormos, Chad M. Gichinga, Moses G. Maitra, Rangan Runyon, Scott P. Thomas, James B. Brieaddy, Lawrence E. Mascarella, S. Wayne Navarro, Hernán A. Carroll, F. Ivy |
author_sort | Kormos, Chad M. |
collection | PubMed |
description | [Image: see text] JDTic analogues 4–15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had K(e) = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the K(e) = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders. |
format | Online Article Text |
id | pubmed-4161151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-41611512015-08-18 Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: In Vitro Pharmacology and ADME Profile Kormos, Chad M. Gichinga, Moses G. Maitra, Rangan Runyon, Scott P. Thomas, James B. Brieaddy, Lawrence E. Mascarella, S. Wayne Navarro, Hernán A. Carroll, F. Ivy J Med Chem [Image: see text] JDTic analogues 4–15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had K(e) = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the K(e) = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders. American Chemical Society 2014-08-18 2014-09-11 /pmc/articles/PMC4161151/ /pubmed/25133923 http://dx.doi.org/10.1021/jm5008177 Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | Kormos, Chad M. Gichinga, Moses G. Maitra, Rangan Runyon, Scott P. Thomas, James B. Brieaddy, Lawrence E. Mascarella, S. Wayne Navarro, Hernán A. Carroll, F. Ivy Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: In Vitro Pharmacology and ADME Profile |
title | Design, Synthesis, and Biological
Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide
(JDTic) Analogues: In Vitro Pharmacology and ADME Profile |
title_full | Design, Synthesis, and Biological
Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide
(JDTic) Analogues: In Vitro Pharmacology and ADME Profile |
title_fullStr | Design, Synthesis, and Biological
Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide
(JDTic) Analogues: In Vitro Pharmacology and ADME Profile |
title_full_unstemmed | Design, Synthesis, and Biological
Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide
(JDTic) Analogues: In Vitro Pharmacology and ADME Profile |
title_short | Design, Synthesis, and Biological
Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide
(JDTic) Analogues: In Vitro Pharmacology and ADME Profile |
title_sort | design, synthesis, and biological
evaluation of (3r)-1,2,3,4-tetrahydro-7-hydroxy-n-[(1s)-1-[[(3r,4r)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide
(jdtic) analogues: in vitro pharmacology and adme profile |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161151/ https://www.ncbi.nlm.nih.gov/pubmed/25133923 http://dx.doi.org/10.1021/jm5008177 |
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