Document Detail

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.
MedLine Citation:
PMID:  20466543     Owner:  NLM     Status:  MEDLINE    
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.
Jyothi Matharu; Jun Oki; David R Worthen; Quentin R Smith; Peter A Crooks
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Publication Detail:
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:
Title:  Bioorganic & medicinal chemistry letters     Volume:  20     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-04     Completed Date:  2010-09-13     Revised Date:  2013-07-31    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  3688-91     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Ltd. All rights reserved.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
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MeSH Terms
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
Protein Binding
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Large Neutral Amino Acid-Transporter 1; 0/Myeloablative Agonists; 0/Norbornanes; 148-82-3/Melphalan

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