Novel glycine transporter type-2 reuptake inhibitors. Part 1: alpha-amino acid derivatives.
A variety of alpha-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) was evaluated. An array of substituents at the chiral center was studied and overall, L-phenylalanine was identified as the preferred amino acid residue. Compounds prepared from l-amino acids were more potent GlyT-2 inhibitors than analogs derived from the corresponding d-amino acids. Introducing an achiral amino acid such as glycine, or incorporating geminal substitution in the alpha-position, led to a significant reduction in GlyT-2 inhibitory properties.
Wolin
Ronald L
RL
Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. rwolin@prdus.jnj.com
Venkatesan
Hariharan
H
Tang
Liu
L
Santillán
Alejandro
A
Barclay
Tristin
T
Wilson
Sandy
S
Lee
Doo Hyun
DH
Lovenberg
Timothy W
TW
D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000235:genetics; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology
D026921:Amino Acid Transport Systems, Neutral; D000596:Amino Acids; D050487:Glycine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D010649:Phenylalanine; D005998:Glycine