Summary of work: The identity and function of regulated blood-brain barrier transporters for essential nutrients and drugs were examined in relation to aging and disease and in order to develop new drugs that are shuttled into brain via carrier-mediated transport. Two basic amino acid transporters (CAT-1 and CAT-2) were cloned from the BBB, as well as a putative accessory or modulatory subunit (4F2). mRNA levels of the CAT-1 transporter were shown to decrease with age after birth. The substrate selectivity of the blood-brain barrier large neutral amino acid transporter was examined and used to develop new high affinity amino acid drugs that are shuttle rapidly into brain via carrier-mediated transport. One such compound, D,L-NAM, exhibited 20-40 fold greater brain uptake than its clinical analog, L-melphalan, and was developed further for brain antitumor testing. A similar compound, 4-chloro-kynurenine, was examined as a neuroprotective agent against excitotoxic brain damage. A computer model of the binding site of the BBB neutral amino acid transporter was developed to aid in the design of new drugs that are selectively shuttled into brain by facilitated transport.
NIH ExPorter
NIH ExPorter