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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
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.
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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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