| Regiospecific and conformationally restrained analogs of melphalan and DL-2-NAM-7 and their affinities for the large neutral amino acid transporter (system LAT1) of the blood-brain barrier. | |
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MedLine Citation:
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PMID: 20466543 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Regiospecific and conformationally restrained analogs of melphalan and DL-2-NAM-7 have been synthesized and their affinities for the large neutral amino acid transporter (LAT1) of the blood-brain barrier have been determined to assess their potential for accessing the CNS via facilitated transport. Several analogs had K(i) values in the range 2.1-8.5 microM with greater affinities than that of either L-phenylalanine (K(i)=11 microM) or melphalan (K(i)=55 microM), but lower than DL-2-NAM-7 (K(i)=0.08 microM). The results indicate that regiospecific positioning of the mustard moiety on the aromatic ring in these analogs is very important for optimal affinity for the large neutral amino acid transporter, and that conformational restriction of the DL-2-NAM-7 molecule in benzonorbornane and indane analogs leads to 25- to 60-fold loss, respectively, in affinity. |
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Authors:
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Jyothi Matharu; Jun Oki; David R Worthen; Quentin R Smith; Peter A Crooks |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-04-24 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 20 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-04 Completed Date: 2010-09-13 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: 3688-91 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Transport Blood-Brain Barrier / metabolism* Brain / metabolism Large Neutral Amino Acid-Transporter 1 / chemistry*, metabolism Melphalan / analogs & derivatives, chemistry*, pharmacokinetics Molecular Conformation Molecular Structure Myeloablative Agonists Norbornanes Protein Binding Rats Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
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R01 NS052484/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Large Neutral Amino Acid-Transporter 1; 0/Myeloablative Agonists; 0/Norbornanes; 148-82-3/Melphalan |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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