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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081662-03
Application #
7796863
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Dunsmore, Sarah
Project Start
2008-06-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$304,020
Indirect Cost
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Daeffler, Kristina N-M; Lester, Henry A; Dougherty, Dennis A (2012) Functionally important aromatic-aromatic and sulfur-ýý interactions in the D2 dopamine receptor. J Am Chem Soc 134:14890-6
Lester, Henry A; Miwa, Julie M; Srinivasan, Rahul (2012) Psychiatric drugs bind to classical targets within early exocytotic pathways: therapeutic effects. Biol Psychiatry 72:907-15
Van Arnam, Ethan B; Lester, Henry A; Dougherty, Dennis A (2011) Dissecting the functions of conserved prolines within transmembrane helices of the D2 dopamine receptor. ACS Chem Biol 6:1063-8
Torrice, Michael M; Bower, Kiowa S; Lester, Henry A et al. (2009) Probing the role of the cation-pi interaction in the binding sites of GPCRs using unnatural amino acids. Proc Natl Acad Sci U S A 106:11919-24