Structure based drug discovery for Dopamine D Receptor Selective Ligands

Summary The neurotransmitter dopamine DA controls many central nervous system functions through three major pathways in the brain the tuberoinfundibular the nigrostriatal and the mesocorticolimic mesocortical and mesolimbic Each is associated with different processes and dysfunction can lead to varying diseases and disorders There are five known DA receptors D D R is one of the most abundant DA receptors in the brain and is thus an important pharmacological target for many central nervous system diseases Most of the clinically efficacious antipsychotics used for the treatment of schizophrenia and Parkinsonandapos s disease which are associated with the mesocorticolimbic and nigrostriatal pathways are D R agonists or antagonists In addition several drugs abused by humans ie psychostimulants such as cocaine and methamphetamine affect DA neurotransmission in the mesolimbic pathway due to their effects on reward related behaviours Therefore D R is also a focus for the discovery of pharmacological treatments for substance abuse of a certain class of drugs and addiction disorders for which there are none currently available The goal of this proposal is to clone express and purify active state stabilized D R in quantities amenable to pursue initial crystallization trials To obtain active state stabilized protein crystals D R will be bound with agonist and complexed with purified G protein and or a stabilizing nanobody This will enable our longer term goal of x ray crystallographic structure determination and the discovery of D R selective small molecule ligands for the treatment of substance abuse disorders This proposal is in response to the Funding Opportunity Announcement PA PHS Omnibus Solicitation of the NIH CDC FDA and ACF for Small Business Innovation Research Grant Appplications Parent SBIR R R Narrative Many drugs abused by humans ie psychostimulants such as cocaine and methamphetamine affect dopamine neurotransmission via their effect on reward related behaviours We propose to determine the dimensional structure of active state stabilized dopamine D receptor This will allow us to pursue structure guided drug discovery and development of small molecules targeting D dopamine receptor for the treatment of substance abuse disorders for which there are no current pharmacological treatments