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Quantitative Insight into the Design of Compounds Recognized by the L ‐Type Amino Acid Transporter 1 (LAT1)
Author(s) -
Ylikangas Henna,
Malmioja Kalle,
Peura Lauri,
Gynther Mikko,
Nwachukwu Emmanuel O.,
Leppänen Jukka,
Laine Krista,
Rautio Jarkko,
LahtelaKakkonen Maija,
Huttunen Kristiina M.,
Poso Antti
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402281
Subject(s) - prodrug , transporter , amino acid , chemistry , blood–brain barrier , transmembrane protein , amino acid transporter , biochemistry , combinatorial chemistry , stereochemistry , biology , gene , receptor , central nervous system , neuroscience
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.