Behrend F. Lundt

Synthesis of novel GABA uptake inhibitors. Part 6 : Preparation and evaluation of N-Ω asymmetrically substituted nipecotic acid derivatives

In a previous series of potent GABA uptake inhibitors published from this laboratory, we noticed that asymmetry in the substitution pattern of the bis-aromatic moiety in known GABA uptake inhibitors such as 4 [1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid] and 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid] was beneficial for high affinity. This led us to investigate asymmetric analogues of known symmetric GABA uptake inhibitors in which one of the aryl groups has been exchanged with an alkyl, alkylene or cycloalkylene moiety as well as other modifications in the lipophilic part. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound, and it was found that several of the novel compounds inhibit GABA uptake as potently as their known symmetrical reference analogues. Several of the novel compounds were also evaluated for their ability to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in vivo. Some of the compounds, for example 18 [(R)-1-(2-(((1,2-bis(2-fluorophenyl)ethylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid], show a high in vivo potency and protective index comparable with that of our recently launched anticonvulsant product, 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid], and may therefore serve as second-generation drug candidates.

The synthesis of novel GABA uptake inhibitors. Part 2. Synthesis of 5-hydroxytiagabine, a human metabolite of the GABA reuptake inhibitor tiagabine

Abstract (R)-1-(4-(2,5-Dihydro-3-methyl-5-oxothien-2-ylidene)-4-(3-methyl-2-thienyl)butyl)-3-piperidinecarboxylic acid (5-hydroxytiagabine) 13, has been prepared in 8 steps from 2-bromo-3-methylthiophene 3. Key steps are Grignard reactions, displacement of heteroaromatic chlorine with methoxy, and simultaneously demethylation and opening of a hydroxymethylcyclopropane with bromotrimethylsilane. An alternative approach involving acylation of 2-lithio-3-methylthiophene 17a was found less satisfying. A metalloporphyrin assisted hydroxylation of tiagabine 1 also yielded the target metabolite. The structure of 5-hydroxytiagabine was confirmed by NMR-data including COSY, ROESY, HMQC and HMBC experiments.