Targeting cerebellar, alpha6-containing GABA-A receptors with novel compounds based on computational pharmacophore screening as potential therapy for essential tremor

Y-Aminobutyric acid type A (GABA-A) receptors are GABA-gated ion channels that are assembled of 5 (out of a set of 19) subunits, with six possible different alpha subunits. These differently assembled subunits lead to receptors with unique pharmacological and physiological properties that also show unique anatomical distribution. Animal models of several neuropsychiatric conditions suggest that compounds selectively activating, or positively modulating, cerebellar alpha6-containing GABA-A receptors can have highly beneficial effects on different diseases. For the case of essential tremor, flumazenil reduces harmaline induced tremor in wild-type mice, but not in alpha6-knock out mice. Other potential indications are tic disorders, and some unwanted ethanol effects. Therefore, alpha6-selective compounds could possibly open up several new treatment options for diverse neuropsychiatric disorders.The investigated substances are newly synthesized molecules, that were discovered using pharmacophore modeling. They are tested both on alpha1- and alpha6-containing GABA-A receptors, which are expressed heterologously in Xenopus laevis oocytes using two electrode voltage clamp recordings. We have so far identified several novel positive allosteric modulators which enhance the response to the endogenous ligand GABA in alpha6-containing GABA-A receptors with higher potency and/or efficacy than in alpha1-containing GABA-A receptors. With this work we pave the path towards developing novel ligands that might be useful in treating neuropsychiatric conditions involving central and peripheral alpha6-containing GABA-A receptors.