Understanding drug-receptor interactions in the nervous system

ORGN 394

Dennis A. Dougherty, dadougherty@caltech.edu, Division of Chemistry and Chemical Engineering, California Institute of Technology, Mail Code 164-30 Cr, 164-30, Pasadena, CA 91125
Chemical-scale insights into the mechanisms of action of neuroreceptors and ion channels are difficult to obtain. These complex, membrane-bound, typically multisubunit proteins are not amenable to crystallography or NMR, and so structural information is minimal. Yet, these are the molecules of memory, thought, and sensory perception, and the targets of therapeutic approaches to Parkinson's, Alzheimer's, schizophrenia, ADHD, addiction, and many other disorders. Using a combination of organic synthesis, molecular biology, electrophysiology, and computer modeling, we have developed general approaches to unraveling the mysteries of these critical receptors. We will describe studies of both drug binding and channel gating in receptors for nicotine, serotonin, and GABA. We will also discuss a different view of small molecule-protein interactions that is necessary in studies of receptors vs. the more classical, enyzme-substrate models.