γ-Aminobutyric Acid(C) (GABAC) Selective Antagonists Derived from the Bioisosteric Modification of 4-Aminocyclopent-1-enecarboxylic Acid: Amides and Hydroxamates

Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4-ACPHA (10a, IC50 = 13 μM) and 4-ACPAM (11a, IC50 = 10 μM). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.