Structure-based drug discovery for Dopamine D2 Receptor Selective Ligands

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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, D2 (D2R) 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 Parkinson's disease, which are associated with the mesocorticolimbic and nigrostriatal pathways, are D2R 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 D2R 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 D2R in quantities amenable to pursue initial crystallization trials. To obtain active-state stabilized protein crystals, D2R 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 D2R selective small molecule ligands for the treatment of substance abuse disorders. This proposal is in response to the Funding Opportunity Announcement PA-16- 302: PHS 2016-02 Omnibus Solicitation of the NIH, CDC, FDA, and ACF for Small Business Innovation Research Grant Appplications (Parent SBIR [R43/R44]).