Synthesis of alkyl-substituted arecoline derivatives as gamma-aminobutyric acid uptake inhibitors.
A series of N-methyltetrahydropyridine-3-carboxylic acids and methyl esters have been synthesized and biologically evaluated. Arecoline (6) was lithiated with LDA in THF to give 7, which was treated with various alkyl halides to afford exclusively the alpha-substituted products 8a-g. Thermodynamic reaction of 7 with carbonyl compounds gave the corresponding 5-substituted arecoline derivatives 10a-q. When phenyldiazonium tetrafluoroborate was used as electrophile, 8h and 9 were obtained. The relative stereochemistry of 10j-o was established by 1H NMR spectroscopy. Compound 12 was obtained by condensation of the silylketene acetal 11 with N-acetylindoxyl. Dehydration of 10a-c yielded 14a-c, respectively. Deprotection of the esters 14a, 14c, and 15 followed by chromatography on an ion-exchange resin gave the amino acids 16a, 16c, and 16d. The alcohol 17 was obtained by LiAlH4 reduction of the corresponding ester 14c. The amino acid 16c displayed a marked inhibitory effect on the synaptosomal uptake of gamma-amino[3H]butyric acid ([3H]GABA). The type of inhibition was competitive with a Ki of 12.9 microM. Compound 16d also inhibited [3H]GABA uptake but was about 10 times weaker than 16c. None of the biologically tested compounds (8a-g, 9, 10a-q, 12, 14a-c, 16a-d, 17) showed any effect in binding studies using [3H]GABA as ligand.
D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001115:Arecoline; D005680:gamma-Aminobutyric Acid