Potent 4-Aryl- or 4-Arylalkyl-Substituted 3-Isoxazolol GABAAAntagonists: Synthesis, Pharmacology, and Molecular Modeling

We have previously described a series of competitive GABAA antagonists derived from the low-efficacy partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 4). The 2-naphthylmethyl analogue, 4-(2-naphthylmethyl)-5-(4-piperidyl)-3-isoxazolol (5), provided affinity for the GABAA receptor site higher than that of the standard GABAA receptor antagonist, SR 95531 (3). Molecular modeling studies of these compounds exposed a cavity at the receptor recognition site capable of accommodating aromatic groups of substantial size in the 4-position in the 3-isoxazolol ring. Here we present a series of analogues of 5, with various substituents in different positions in the naphthyl ring system (6a−k), and compounds with aromatic substituents directly attached to the 4-position of the 3-isoxazolol ring (7l−n). The compounds have been pharmacologically characterized using receptor-binding assays and electrophysiological whole-cell patch-clamp techniques. All of the tested compounds show affinity for the GABAA receptor site...