title: Amino acid ester prodrugs conjugated to the α-carboxylic acid group do not display affinity for the L-type amino acid transporter 1 (LAT1).
abstract: L-type amino acid transporter (LAT1) is an intriguing target for carrier-mediated transport of drugs as it is highly expressed in the blood-brain barrier and also in various types of cancer. Several studies have proposed that in order for compounds to act as LAT1 substrates they should possess both negatively charged α-carboxyl and positively charged α-amino groups. However, in some reports, such as in two recent publications describing an isoleucine-quinidine ester prodrug (1), compounds having no free α-carboxyl group have been reported to exhibit high affinity for LAT1 in vitro. In the present study, 1 was synthesized and its affinity for LAT1 was evaluated both with an in situ rat brain perfusion technique and in the human breast cancer cell line MCF-7 in vitro. 1 showed no affinity for LAT1 in either model nor did it show any affinity for LAT2 in an in vitro study. Our results confirm the earlier reported requirements for LAT1 substrates. Thus drugs or prodrugs with substituted α-carboxyl group cannot bind to LAT with high affinity.
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: jarkko.rautio@uef.fi.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Kärkkäinen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
mesh_terms: D027241:Amino Acid Transport System y+L / Q000737:chemistry / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D004952:Esters; D006801:Humans; D007532:Isoleucine / Q000737:chemistry* / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry* / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D011355:Prodrugs; D011485:Protein Binding; D011802:Quinidine / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D027241:Amino Acid Transport System y+L; D000596:Amino Acids; D004952:Esters; D027283:Large Neutral Amino Acid-Transporter 1; D011355:Prodrugs; D007532:Isoleucine; D011802:Quinidine
keywords: Isoleucine; L-type amino acid transporter 1; LAT1; Prodrug; Quinidine