GABA-uptake inhibitors: construction of a general pharmacophore model and successful prediction of a new representative.
A model for the pharmacophore of GABA-uptake inhibitors was established using published structure-activity data and molecular modeling. The model accounted for the activities of different classes of GABA-uptake inhibitors. Analogues of guvacine substituted at position 6 were synthesized in order to confirm the model. 6-(3,3-Di-phenylpropyl)guvacine (30f), which fit well with the pharmacophore, had an in vitro IC50 of 0.1 microM. This value is as good as those of the best GABA-uptake inhibitors known today.
N'Goka
V
V
Laboratoire de Pharmacochimie Moléculaire, Centre de Neurochimie du CNRS, Strasbourg, France.
Schlewer
G
G
Linget
J M
JM
Chambon
J P
JP
Wermuth
C G
CG
D000818:Animals; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D018756:GABA Antagonists; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009539:Nicotinic Acids; C070482:6-(3,3-diphenylpropyl)guvacine; C015910:guvacine; D005680:gamma-Aminobutyric Acid