Exploring the DS2 Scaffold for GABA_A Receptor Modulation: Progress toward the Development of a GABA_A δ-Subunit...

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-a]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 N-methylated pyrrolyl ring (1e) converted the pharmacological profile from positive to negative allosteric modulation. Compound 1e exhibited no activity at selected γ₂-containing GABA_AR subtypes, indicating δ-GABA_AR selectivity. The ability of 1e 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 1e as a lead compound for reducing pathophysiologically excessive tonic inhibition.