A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.

The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol (THAZ), has previously been shown to be a weak GABA(A) and glycine receptor antagonist. In the present study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT(2A) and 5-HT(2C) receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT(2C) antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT(2A) and/or 5-HT(2C) receptors, the isoxazoles 3d and 4d constitute interesting leads for further medicinal chemistry development.

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γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA). In general, all structural modifications performed on HOCPCA led to reduced affinity. In contrast, introduction of diaromatic substituents into the 4-position of T-HCA led to high-affinity analogs (medium nanomolar K) for the GHB high-affinity binding sites as the most high-affinity analogs reported to date. The SAR data formed the basis for a three-dimensional pharmacophore model for GHB ligands, which identified molecular features important for high-affinity binding, with high predictive validity. These findings will be valuable in the further processes of both target characterization and ligand identification for the high-affinity GHB binding sites.

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