Novel glycine transporter type-2 reuptake inhibitors. Part 1: alpha-amino acid derivatives |
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Authors: | Wolin Ronald L Venkatesan Hariharan Tang Liu Santillán Alejandro Barclay Tristin Wilson Sandy Lee Doo Hyun Lovenberg Timothy W |
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Affiliation: | Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. rwolin@prdus.jnj.com |
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Abstract: | 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. |
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