4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists: synthesis, pharmacology, and structure-activity relationships.
A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists have been synthesized and pharmacologically characterized. The meta-phenyl-substituted compounds 9k and 9m and the para-phenoxy-substituted compound 9l all display high affinities (Ki=10-70 nM) and antagonist potencies in the low nanomolar range (Ki=9-10 nM). These potencies are significantly higher than those of previously reported 4-PIOL antagonists and considerably higher than that of the standard GABAA antagonist SR 95531.
Frølund
Bente
B
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark. bfr@farma.ku.dk
Jensen
Lars S
LS
Storustovu
Signe I
SI
Stensbøl
Tine B
TB
Ebert
Bjarke
B
Kehler
Jan
J
Krogsgaard-Larsen
Povl
P
Liljefors
Tommy
T
D000818:Animals; D005260:Female; D058787:GABA-A Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014981:Xenopus
D058787:GABA-A Receptor Antagonists; D007555:Isoxazoles; D010880:Piperidines; D011724:Pyridazines; C049853:gabazine