title: Quantitative insight into the design of compounds recognized by the L-type amino acid transporter 1 (LAT1).
abstract: L-Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood-brain barrier (BBB), where it ensures the transport of hydrophobic acids from the blood to the brain. Due to its unique substrate specificity and high expression at the BBB, LAT1 is an intriguing target for carrier-mediated transport of drugs into the brain. In this study, a comparative molecular field analysis (CoMFA) model with considerable statistical quality (Q(2) =0.53, R(2) =0.75, Q(2) SE=0.77, R(2) SE=0.57) and good external predictivity (CCC=0.91) was generated. The model was used to guide the synthesis of eight new prodrugs whose affinity for LAT1 was tested by using an in situ rat brain perfusion technique. This resulted in the creation of a novel LAT1 prodrug with L-tryptophan as the promoiety; it also provided a better understanding of the molecular features of LAT1-targeted high-affinity prodrugs, as well as their promoiety and parent drug. The results obtained will be beneficial in the rational design of novel LAT1-binding prodrugs and other compounds that bind to LAT1.
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio (Finland).
authors.forename: Henna
authors.initials: H
authors.lastname: Ylikangas
authors.forename: Kalle
authors.initials: K
authors.lastname: Malmioja
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.forename: Emmanuel O
authors.initials: EO
authors.lastname: Nwachukwu
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D014364:Tryptophan / Q000737:chemistry
chemical_list: D027283:Large Neutral Amino Acid-Transporter 1; D011355:Prodrugs; D014364:Tryptophan
keywords: 3 D QSAR; CoMFA; LAT1; drug design; prodrugs