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 A Rs) are potential drug targets in the treatment of several neurological disorders with altered tonic inhibition. Only a few compounds exhibit δ-GABA A R 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 α 4 β 1 δ GABA A R, 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 γ 2 -containing GABA A R subtypes, indicating δ-GABA A R selectivity. The ability of 1e to reduce the GABA currents of recombinant receptors carrying α 4 - 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.