Orphan GPCRs as targets for drugs to treat addiction

DESCRIPTION (provided by applicant): Nura is a new biotechnology company focused on the development of drugs against orphan GPCRs in the CMS. We have identified the distribution of most orphan GPCRs in the brain and developed novel high throughput gene knockout procedures to rapidly identify GPCR phenotypes to gain insight into whether the receptors might be important targets for drug development. Two orphan GPCRs, PGR486 and PGR854, in particular showed unique properties in our initial studies. They are primarily expressed in brain and knockout of the genes for these receptors produces phenotypes related to complex CNS behaviors such as drug sensitivity and tolerance, anxiety, fear and memory acquisition. These GPCRs may provide unique targets for the development of drugs to treat substance abuse, addiction, anxiety and other stress related disorders. The goal of this phase I SBIR is to develop technologies that will allow us to use these GPCRs as targets for drug discovery. For both receptors we will develop cell-based assays that will allow for detection of the activation of these receptors by small molecule compounds. These assays will be formatted for high throughput screening (HTS) of compound libraries and then in proof of principle studies we will screen the receptors with limited size drug libraries. These studies will lay the foundation for future studies (phase II SBIR) to identify agonists and antagonists against these orphan GPCRs and to use them in studies of animal behavior and physiology to further define the functions of these receptors and to eventually developed these compounds into drugs to treat alcohol abuse and addiction.