Physical Organic Chemistry on the Brain

The challenges to obtaining chemical-scale information on the molecules of neuroscience are considerable. Most targets are complex integral membrane proteins that are not amenable to direct structural characterization. However, by combining the tools of organic synthesis, molecular biology, and electrophysiology, rational and systematic structure−function studies can be performed in what we have termed physical organic chemistry on the brain. Using these tools, we have probed hydrophobic effects, hydrogen bonding, cation−π interactions, and conformational changes associated with channel gating. The insights gained provide important guidance for drug discovery efforts targeting ion channels and neuroreceptors and mechanistic insights for the complex proteins of neuroscience.