Activity of 2-azaspiro[4.5]decane-6-carboxylates as GABA-uptake inhibitors

Novel GABA analogous spirocyclic amino acid esters 7a-d and 8a-d were prepared and investigated for interaction with GABA-A and GABA-B receptors as well as the GABA uptake system. Starting from known bromoethyl lactones 1 or 2 and arylalkylamines spirocyclic hydroxyalkyl lactams 3a-d and 4a-d were obtained and reduced by LiAlH4 to yield spirocyclic hydroxymethyl pyrrolidines 5a-d and 6a-d. Oxidation by Jones reagent followed by subsequent esterification gave the title compounds 7a-d and 8a-d which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acid esters 7a-d and 8a-d 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 upon the length of the alkyl chain in N-arylalkyl substituents and upon the ring size of underlying spirocyclic system.