title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Matharu
authors.forename: Jun
authors.initials: J
authors.lastname: Oki
authors.forename: David R
authors.initials: DR
authors.lastname: Worthen
authors.forename: Quentin R
authors.initials: QR
authors.lastname: Smith
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry* / Q000378:metabolism; D008558:Melphalan / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D019653:Myeloablative Agonists; D009636:Norbornanes; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D027283:Large Neutral Amino Acid-Transporter 1; D019653:Myeloablative Agonists; D009636:Norbornanes; D008558:Melphalan
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