Summary Most general anesthetics and classical benzodiazepines act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . Direct structural information for how these drugs work at their physiological receptor sites is absent for general anesthetics. Here we present high-resolution structures of GABA A receptors bound to intravenous anesthetic, benzodiazepine, and inhibitory modulators. These structures were solved in a lipidic environment and complemented by electrophysiology and molecular dynamics simulations. Structures in complex with the anesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, shared in part by the benzodiazepine diazepam. Structures bound by antagonistic benzodiazepine-site ligands identify a novel membrane binding site for diazepam and suggest an allosteric mechanism for anesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinctive mechanisms to potentiate inhibitory signaling in the brain.

Highlights d The a3b4 ganglionic nicotinic receptor is a target for antiaddiction therapeutics d Receptor structures were determined in a functionally supportive lipidic environment d Comparisons with the a4b2 subtype suggest principles underlying ligand selectivity d Lateral portals in the intracellular domain facilitate ion permeation

Diverse and controllable pathways induced by palladium-catalyzed intramolecular Heck reaction of N-vinylacetamides for the synthesis of nitrogen-containing products in reasonable to high yields via tuning the phosphine ligands and bases are reported. Domino reactions including unique β-N-Pd elimination, 1,4-Pd migration, or direct acyl C-H bond functionalization were found to be involved forming different products, respectively. Given the ability of using the same starting material to generate diverse products via completely different chemoselective processes, these current methodologies offer straightforward access to valuable nitrogen-containing products under mild reaction conditions as well as inspire the discovery of novel reactions.