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Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists

[Image: see text] The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity...

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Autores principales: Xiao, Jingbo, Free, R. Benjamin, Barnaeva, Elena, Conroy, Jennie L., Doyle, Trevor, Miller, Brittney, Bryant-Genevier, Marthe, Taylor, Mercedes K., Hu, Xin, Dulcey, Andrés E., Southall, Noel, Ferrer, Marc, Titus, Steve, Zheng, Wei, Sibley, David R., Marugan, Juan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315423/
https://www.ncbi.nlm.nih.gov/pubmed/24666157
http://dx.doi.org/10.1021/jm500126s
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author Xiao, Jingbo
Free, R. Benjamin
Barnaeva, Elena
Conroy, Jennie L.
Doyle, Trevor
Miller, Brittney
Bryant-Genevier, Marthe
Taylor, Mercedes K.
Hu, Xin
Dulcey, Andrés E.
Southall, Noel
Ferrer, Marc
Titus, Steve
Zheng, Wei
Sibley, David R.
Marugan, Juan J.
author_facet Xiao, Jingbo
Free, R. Benjamin
Barnaeva, Elena
Conroy, Jennie L.
Doyle, Trevor
Miller, Brittney
Bryant-Genevier, Marthe
Taylor, Mercedes K.
Hu, Xin
Dulcey, Andrés E.
Southall, Noel
Ferrer, Marc
Titus, Steve
Zheng, Wei
Sibley, David R.
Marugan, Juan J.
author_sort Xiao, Jingbo
collection PubMed
description [Image: see text] The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders.
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spelling pubmed-43154232015-03-25 Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists Xiao, Jingbo Free, R. Benjamin Barnaeva, Elena Conroy, Jennie L. Doyle, Trevor Miller, Brittney Bryant-Genevier, Marthe Taylor, Mercedes K. Hu, Xin Dulcey, Andrés E. Southall, Noel Ferrer, Marc Titus, Steve Zheng, Wei Sibley, David R. Marugan, Juan J. J Med Chem [Image: see text] The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders. American Chemical Society 2014-03-25 2014-04-24 /pmc/articles/PMC4315423/ /pubmed/24666157 http://dx.doi.org/10.1021/jm500126s Text en Copyright © 2014 U.S. Government This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Xiao, Jingbo
Free, R. Benjamin
Barnaeva, Elena
Conroy, Jennie L.
Doyle, Trevor
Miller, Brittney
Bryant-Genevier, Marthe
Taylor, Mercedes K.
Hu, Xin
Dulcey, Andrés E.
Southall, Noel
Ferrer, Marc
Titus, Steve
Zheng, Wei
Sibley, David R.
Marugan, Juan J.
Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists
title Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists
title_full Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists
title_fullStr Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists
title_full_unstemmed Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists
title_short Discovery, Optimization, and Characterization of Novel D(2) Dopamine Receptor Selective Antagonists
title_sort discovery, optimization, and characterization of novel d(2) dopamine receptor selective antagonists
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315423/
https://www.ncbi.nlm.nih.gov/pubmed/24666157
http://dx.doi.org/10.1021/jm500126s
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