title: Structure-activity relationship study of compounds binding to large amino acid transporter 1 (LAT1) based on pharmacophore modeling and in situ rat brain perfusion.
abstract: Large neutral amino acid transporter 1 (LAT1) is predominantly expressed at the blood-brain barrier and it has a major role in transporting neutral amino acids into the brain. LAT1 has the potential to function as a drug carrier for improved drug brain delivery which makes it an intriguing target protein for central nervous system disorders, e.g., Alzheimer's disease, Parkinson's disease and brain tumors. In this study, a 3D pharmacophore was generated for a set of LAT1 substrates whose binding affinities were studied using competitive inhibition of the brain uptake of [¹⁴C]-L-leucine with an in situ rat brain perfusion method. The pharmacophore highlights the most important molecular features shared by efficient LAT1-binding compounds and elucidates their 3D-arrangement in detail. This clarifies the structure-activity relationships of LAT1 substrates and provides insights for making a binding hypothesis. The results can be further applied in the design of novel efficient LAT1 substrates.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: Henna.Ylikangas@uef.fi.
authors.forename: Henna
authors.initials: H
authors.lastname: Ylikangas
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Kalle
authors.initials: K
authors.lastname: Malmioja
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D006860:Hydrogen Bonding; D007700:Kinetics; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry* / Q000378:metabolism; D007930:Leucine / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018697:Nootropic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010477:Perfusion; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D027283:Large Neutral Amino Acid-Transporter 1; D008024:Ligands; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D011355:Prodrugs; D007930:Leucine