Characterization of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling

Novel γ-Aminobutyric Acid ρ1Receptor Antagonists; Synthesis, Pharmacological Activity and Structure−Activity Relationships

“…At α 1 β 2 γ 2L containing GABA A receptors, all compounds displayed only very weak antagonist activity, which is consistent with the reported poor affinity of the GABA A receptor for phosphinic acids. ,, Interestingly, 42 (R = Bn) displays greater antagonist activity at GABA A receptors than any of the other compounds. This is in keeping with the pharmacophore model based on alkyl and aryl substituted 5-(4-piperidyl)isoxazol-3-ol compounds, which includes a large hydrophobic pocket. Thus the affinity of 42 for the GABA A receptor may be enhanced by interaction with this region of the receptor.…”

“…67,72,74 Interestingly, 42 (R ) Bn) displays greater antagonist activity at GABA A receptors than any of the other compounds. This is in keeping with the pharmacophore model based on alkyl and aryl substituted 5-(4-piperidyl)isoxazol-3-ol compounds, 76 which includes a large hydrophobic pocket. Thus the affinity of 42 for the GABA A receptor may be enhanced by interaction with this region of the receptor.…”