GABA UPTAKE INHIBITORS - SYNTHESES AND STRUCTURE ACTIVITY STUDIES ON GABA ANALOGS CONTAINING DIARYLBUTENYL AND DIARYLMETHOXYALKYL N-SUBSTITUENTS

A number of analogues of GABA or B-alanine containing 4,4-diphenyl-3-butenyl (DPB), benzhydryl ethyl ether (BEE), or benzhydryl propyl ether N-substituents have been synthesized and tested as inhibitors of synaptosomal GABA uptake. N-methylation of these analogues resulted in increased potency and reduced pKa II values of the reaction products 4a and 8a, respectively. Incorporation of the alkyl groups of the benzhydryl alkyl ether moieties of N-methyl-N-BEE-B-alanine (12), N-methyl-N-BEE-GABA (8a), or the benzhydryl propyl ether analogue of N-methyl-GABA (10) into the cyclized piperidine analogues gave the less active compounds 17, 18, and 19, respectively. This loss of in vitro activity was most pronounced for the GABA analogues 18 and 19. These results suggest that the basic character of the amino groups as well as the conformational flexibility of the spacer-arm connecting the amino acid 'heads' and the aromatic moieties of this class of GABA uptake inhibitors are factors of importance for GABA uptake affinity.