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

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Abstract
The synthesis of (3RS,4RS)-4-hydroxypiperdine-3-carboxylic acid (4), (3RS,5SR)-5-hydroxypiperidine-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 GABA uptake inhibitors (RS)-piperidine-3-carboxylic acid (nipecotic acid) and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21) are described. (3RS,4SR)-3-hydroxypiperidine-4-carboxylic acid (14), related to the specific GABA agonist piperidine-4-carboxylic acid (isonipecotic acid), was synthesized. The structures of 4, 10, 14, 18 and 20 were established by 270-MHz 1H NMR spectroscopic analyses. The affinity of the compounds for the GABA receptors and for the rat neuronal (synaptosomal) GABA uptake system in vitro was measured. Compound 14 interacted selectively with the GABA receptors but less effectively than isonipecotic acid and the cis-isomer (3RS,4RS)-3-hydroxypiperidine-4-carboxylic acid] 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 was inactive in both test systems.