title: GABA uptake inhibitors containing mono- and diarylmethoxyalkyl N-substituents.
abstract: Analogues of GABA and the GABA uptake inhibitors, nipecotic acid and guvacine, carrying N-(mono)- or N-(diarylmethoxy)alkyl substituents were synthesized and tested in vitro as inhibitors of synaptosomal GABA uptake and GABAA receptor binding. Whereas the N-(diphenylmethoxy)ethyl derivative GABA (compound 23) (see Figures 1 and Scheme 1 for structures) was only a moderately potent inhibitor of GABA uptake, corresponding derivatives of nipecotic acid and guvacine compounds 7e and 16, respectively) were potent inhibitors having IC50 values in the low micromolar range. In the case of 7e, (a) the (R)-isomer (10) was three times more potent than the (S)-isomer (13), (b) the bis-4-chlorophenyl analogue (compound 7g) was more potent than 7e, (c) the introduction of an additional methylene group into the linkage between the nipecotic acid and benzhydryl ether moiety (to give 7f) did not significantly affect in vitro biological activity, and (d) removal of one of the phenyl groups, or replacement of the benzhydryl ether group by the conformationally restrained fluorenyloxy group (to give 7i), resulted in substantial loss of activity. None of the compounds synthesized showed detectable affinity for GABAA receptor sites.
authors.affiliation: Department of Chemistry BC, Royal Danish School of Pharmacy, Copenhagen.
authors.forename: E
authors.initials: E
authors.lastname: Falch
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009539:Nicotinic Acids / Q000494:pharmacology; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014179:Neurotransmitter Uptake Inhibitors; D009539:Nicotinic Acids; D009557:Nipecotic Acids; C015910:guvacine; D005680:gamma-Aminobutyric Acid; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; C045597:SK&F 100330-A