SYNTHESIS AND BIOCHEMICAL-STUDIES OF SPIROCYCLIC AMINO-ACIDS .2. ACTIVITY OF 2-AZASPIRO[5.5]UNDECANE-7-CARBOXYLATES AS GABA-UPTAKE INHIBITORS

Novel GABA analogous spirocyclic amino acids were prepared and investigated for interaction with GABA-A and GABA-B receptors as well as the GABA uptake system. Starting from known bromopropyl lactones and arylalkylamines, spirocyclic hydroxyalkyl lactams were obtained, which were reduced by LiAlH4 to yield spirocyclic hydroxymethyl piperidines. Oxidation by Jones' reagent followed by subsequent esterification gave the title compounds which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acids showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition;revealed a strong dependence of activity on the length of the aikyl chain in N-arylalkyl substituents.