4-Aryl-5-(4-Piperidyl)-3-Isoxazolol GABA_A Antagonists: Synthesis, Pharmacology, and Structure−Activity Relationships

Abstract

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.