Exploring the DS2 Scaffold for GABA _A Receptor Modulation: Progress toward the Development of a GABA _A δ-Subunit Preferring Negative Allosteric Modulator

Extrasynaptic δ-containing γ-aminobutyric acid type A receptors (GABA_ARs) are potential drug targets in the treatment of several neurological disorders with altered tonic inhibition. Only a few compounds exhibit δ-GABA_AR selectivity, among which the imidazo[1,2-<i>a</i>]pyridine compound DS2 constitutes a valuable tool compound. Guided by the recently identified molecular determinants responsible for the positive allosteric modulation by DS2 in the TMD α⁽⁺⁾β^(-) interface of the α₄β₁δ GABA_AR, a series of DS2 analogues were synthesized. Replacement of a thienyl moiety with an <i>N</i>-methylated pyrrolyl ring (<b>1e</b>) converted the pharmacological profile from positive to negative allosteric modulation. Compound <b>1e</b> exhibited no activity at selected γ₂-containing GABA_AR subtypes, indicating δ-GABA_AR selectivity. The ability of <b>1e</b> to reduce the GABA currents of recombinant receptors carrying α₄- and δ-subunit gain-of-function mutations found in patients with neurodevelopmental disorders and epilepsy, as well as being brain-permeable, identifies <b>1e</b> as a lead compound for reducing pathophysiologically excessive tonic inhibition.