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.
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.
Matharu
Jyothi
J
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Oki
Jun
J
Worthen
David R
DR
Smith
Quentin R
QR
Crooks
Peter A
PA
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
D027283:Large Neutral Amino Acid-Transporter 1; D019653:Myeloablative Agonists; D009636:Norbornanes; D008558:Melphalan
Am J Physiol. 1971 Dec;221(6):1629-39
5124307
Expert Rev Anticancer Ther. 2008 May;8(5):707-16
18471044
Cancer Res. 1987 Mar 15;47(6):1571-6
3815357
Eur J Pharm Sci. 2008 Oct 2;35(3):161-74
18656534
J Med Chem. 1983 May;26(5):762-5
6842517
J Neurochem. 1987 Nov;49(5):1651-8
3668544
Eur J Cancer Clin Oncol. 1987 Jun;23(6):783-8
3653195
J Clin Oncol. 2007 Jun 1;25(16):2295-305
17538176
Cancer Res. 1992 Apr 15;52(8):2191-6
1559223
Am J Physiol. 1984 Sep;247(3 Pt 2):H484-93
6476141
J Med Chem. 1987 Mar;30(3):542-7
3820226
Cancer Chemother Pharmacol. 1991;29(2):89-94
1760863
Crit Rev Oncol Hematol. 2009 Mar;69(3):199-210
18602834
J Clin Oncol. 2007 Jun 1;25(16):2306-12
17538177
J Nutr. 2000 Apr;130(4S Suppl):1016S-22S
10736373
J Pharm Sci. 1984 Apr;73(4):457-60
6726628