GPCRs: Chemical-Scale Studies with Unnatural Amino Acids

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DESCRIPTION (provided by applicant): Roughly 40% of human medicines target G protein-coupled receptors (GPCRs), and ongoing research throughout the pharmaceutical industry is focused on these ubiquitous proteins. There are hundreds of different GPCRs, and despite considerable efforts, our knowledge of their structures and modes of action is limited. Over the past decade, our laboratory has developed a powerful methodology for revealing drug- receptor interactions. The method combines organic chemistry, molecular biology, and electrophysiology to incorporate unnatural amino acids into receptors. We have applied the approach to many neuroreceptors and ion channels, with informative and important results. In the present work we propose to apply the unnatural amino acid methodology to the study of GPCRs. Our initial target will be a family of dopamine receptors, which are implicated in treatments for a number of neurological disorders including Parkinson's disease and schizophrenia. The insights gained from this work will be of great value to efforts to develop safer, more efficacious pharmaceuticals that target dopamine receptors in particular, and GPCRs in general. PUBLIC HEALTH RELEVANCE Efforts to develop safer, more efficacious pharmaceuticals are greatly aided by insights into precisely how drugs interact with their target receptors. The present work will provide just such information for the most ubiquitous targets of the pharmaceutical industry. The results will aid in the development of new treatments for Parkinson's disease, schizophrenia, and attention-deficit hyperactivity disorder.