| Discovery and pharmacological characterization of aryl piperazine and piperidine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT1A partial agonists. | |
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MedLine Citation:
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PMID: 19854053 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1(A) partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT(1A) receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1(A) partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT(1A) in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented. |
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Authors:
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David L Gray; Wenjian Xu; Brian M Campbell; Amy B Dounay; Nancy Barta; Susan Boroski; Lynne Denny; Lori Evans; Nancy Stratman; Al Probert |
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Publication Detail:
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Type: Journal Article Date: 2009-10-12 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 19 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-05 Completed Date: 2010-01-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 6604-7 Citation Subset: IM |
Affiliation:
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Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. david.l.gray@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Dopamine
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metabolism Drug Discovery* Ethers / chemical synthesis, chemistry, pharmacology* Molecular Structure Neurotransmitter Uptake Inhibitors / chemical synthesis, chemistry, pharmacology* Piperazines / chemical synthesis, chemistry, pharmacology* Piperidines / chemical synthesis, chemistry, pharmacology* Receptor, Serotonin, 5-HT1A / agonists* Serotonin Plasma Membrane Transport Proteins / metabolism Stereoisomerism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Ethers; 0/Neurotransmitter Uptake Inhibitors; 0/Piperazines; 0/Piperidines; 0/Serotonin Plasma Membrane Transport Proteins; 112692-38-3/Receptor, Serotonin, 5-HT1A |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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