Hydroxy- and amino-substituted piperidinecarboxylic acids as gamma-aminobutyric acid agonists and uptake inhibitors.
The syntheses of (3RS,4RS)-4-hydroxypiperidine-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 gamma-aminobutyric acid (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.
D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D011963:Receptors, GABA-A; D013570:Synaptic Membranes / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D010880:Piperidines; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid