Hydroxy- and amino-substituted piperidinecarboxylic acids as γ-aminobutyric acid agonists and uptake inhibitors

Article abstract of DOI:10.1021/jm00352a012

The syntheses of (3RS, 4RS)-4-hydroxypiperidine-3-carboxylic acid (4), (3RS, 5SRJ-5-hydroxypiperiden-3-carboxylic acid (20), (3RS, 4SR)-4-acetamidopiperidine-3-carboxylic acid (10), and (3RS, 5SR)-5-acetamidopiperidine-3-carboxylic acid (18), related to the specific γ-aminobutyric (GABA) uptake inhibitors (RS)-piperidine-3-carboxylic acid (nipecotic acid) and (3RS, 4SR)-4-hydroxypiperidine-3-carboxylic acid (21), are described. Furthermore, (3RS, 4SR)-3-hydroxypiperidine-4-carboxylic acid (14), related to the specific GABA agonist piperidine-4-carboxylic acid (isonipecotic acid), has been synthesized. The structures of 4, 10, 14, 18, and 20 have been established by 270-MHz ¹H NMR spectroscopic analyses. The affinity of the compounds for the GABA receptors and for the neuronal (synaptosomal) GABA uptake system in vitro has been measured. Compound 14 interacts selectively with the GABA receptors but less effectively than isonipecotic acid and the cis-isomer 22. Compounds 4, 18, and 20 are inhibitors of the GABA uptake system, although much weaker than nipecotic acid and (3RS, 4SR)-4-hydroxypiperidine-3-carboxylic acid (21). Compound 10 is inactive in both test systems.