The G-protein gated inwardly rectifying potassium (GIRK, Kir-3) channels are members of a large family of inwardly rectifying potassium channels (Kir1-Kir7) and play a significant role in controlling the neuronal excitation by hyperpolarization of neurons upon activation by G protein-coupled receptors. GIRK channels are comprised of homo- or heterotetramers of four structurally and functionally different subunits (GIRK 1-4). Pharmacological investigations and genetic ablation studies over the years have identified and established the contribution of the GIRK 1/2 channel subunit, predominantly found in brain, in the pathophysiology of various neurological disorders including, but not limited to, epilepsy, anxiety, Parkinson's, pain, reward and addiction. Previously, our laboratory has identified urea and amide-based derivative as first-in-class GIRK 1/2 small molecule activators which led to an increased understanding of GIRK channel functionality and their therapeutic potential. However, these compounds have limitations for in vivo utility due to pharmacokinetic liabilities and suboptimal selectivity for GIRK 1/2 subunit over other units. This poster details our work in the design, synthesis, and characterization of novel tetrazole based GIRK 1/2 channel activators resulting in multiple compounds with high potency and efforts to improve their pharmacokinetic properties.

Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazolo-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators

256th National Meeting (2018)

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