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.
Fleischhacker
W
W
Institute of Pharmaceutical Chemistry, University of Vienna, Austria.
Lauritz
S
S
Urban
E
E
Baumann
P
P
Bittiger
H
H
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002264:Carboxylic Acids; D014179:Neurotransmitter Uptake Inhibitors; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D013141:Spiro Compounds; D005680:gamma-Aminobutyric Acid