br Significance Dysregulation of dopamine
Significance Dysregulation of dopamine homeostasis contributes to Parkinson's disease (PD). The nuclear receptor Nurr1 plays a central role in dopamine homeostasis, regulating the transcription of cell cycle regulation governing the synthesis, packaging, and reuptake of dopamine. Efforts to capitalize on Nurr1's potential as a therapeutic target for PD have been hampered by the absence of a defined ligand-binding pocket within the receptor. We found that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds to Nurr1 within a non-canonical pocket, forming a covalent adduct as the 5,6-indolequinone with Cys566. In functional assays, DHI stimulates Nurr1 activity, upregulating the transcription of several genes, including the vesicular monoamine transporter 2. These results suggest that Nurr1 may be regulated by an endogenous metabolite, contradicting previous suggestions that it has no small-molecule regulation.
Acknowledgments This work was supported by grants from the Roger’s Family Foundation, the CTSI, the MAKK Seed Fund, the NIH (R01 NS108404-01), and the Program for Breakthrough Biomedical Research that is partially funded by the Sandler Foundation. We thank Joseph Wagner for helpful discussions. Beamline 8.3.1 at the Advanced Light Source is operated by the University of California Office of the President, Multicampus Research Programs and Initiatives grant MR-15-328599 the National Institutes of Health (R01 GM124149 and P30 GM124169), Plexxikon, and the Integrated Diffraction Analysis Technologies program of the US Department of Energy Office of Biological and Environmental Research. The Advanced Light Source (Berkeley, CA) is a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the US Department of Energy under contract number DE-AC02-05CH11231, Office of Basic Energy Sciences.
Cocaine is a highly addictive psychostimulant associated with intense craving during periods of abstinence. In the US, an estimated 1.4 million individuals aged 12years or older were current (past month) users in 2013 (SAMHSA, 2014). Cocaine use disorder (CUD) is likely to continue, and there is no FDA-approved pharmacologic treatment,, , so it remains a major challenge for clinical and medical research. -THP is a natural product isolated from W.T. Wang, one of the most frequently used traditional herbs to treat drug addiction in China. It has been used in clinical practice in China for >40years for its analgesic, sedating, and hypnotic effects (commercial name: Rotundine™)., Structurally, it resembles two dopamine molecules fused into a tetracyclic alkaloid (). It has low toxicity and a high therapeutic index. Extensive studies, carried out mostly by Chinese scientists, show that it has no affinity for opioid receptors, does not change levels of prostaglandins, binds with moderate affinity to dopamine D1, D2, and D3 receptors, and has dual pharmacological properties of D1 partial agonism and D2 antagonism, with some affinity for α-adrenergic and serotonin receptors. Recently we identified the monodemethylated metabolites -corypalmine (-CP), -corydalmine (-CD), and -isocorypalmine (-ICP) in the serum of mice and rats 30min and 60min after administration of -THP 20mg/kg. It is noteworthy that the partial structures (A, B ring and C, D ring) of these metabolites resemble the structure of dopamine. We have found that the C2-demethylated metabolite -ICP binds to D1 and D5 receptors with high affinity and to D2, D3, and D4 with moderate affinity, and that it is functionally a partial agonist at D1 and D5 and an antagonist at D2, D3, and D4. As -CP and -CD are structurally analogous to -ICP, they are likely to have similar novel pharmacological profiles. We thus hypothesize that -THP is a pro-drug and exerts its behavioral effects via demethylated metabolites. In a previous study, we synthesized -ICP and -SPD by treating -THP with MsOH and methionine (1.2eq) at room temperature. But -CP and -CD were the minor products in this reaction. So total synthesis is the best method to get the tetrahydroprotoberberine derivatives ().