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

Placing the mustard moiety at C-7 of the tetralin ring (5c) affords greatest affinity for the System LAT1 transporter; the more conformationally restrained analogs (6 and 7) of DL-2-NAM-7 had lower affinity than 5c. 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 Ki values in the range 2.1–8.5μM with greater affinities than that of either l-phenylalanine (Ki=11μM) or melphalan (Ki=55μM), but lower than dl-2-NAM-7 (Ki=0.08μM). 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.