The modulation of 5-HT2C receptor (5-HT2CR) function holds a tremendous amount of therapeutic promise for the treatment of diseases of significant unmet medical need, including addiction, anxiety, depression, obesity/eating disorders and schizophrenia. Successful development of 5-HT2CR ligands requires selectivity versus the highly homologous 5-HT2AR and 5-HT2BR, because agonism at these receptors can result in serious CNS and cardiovascular adverse events. The rationale for this proposal is that allosteric modulators of the 5-HT2CR present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner. This novel approach of using allosteric modulators of the 5-HT2CR to develop novel probes and therapeutics is very attractive since it is much easier to achieve high receptor subtype selectivity or even absolute specificity with a ligand binding to the allosteric site than with orthosteric ligands that bind to the endogenous ligand binding site. To date only one compound, PNU-69176E, has been identified via the compound library screening as a 5-HT2CR allosteric modulator. However, the relevant structure-activity relationship (SAR) studies were sparse, and thus our knowledge in this regard is quite limited. Our objective in this application is to optimize and develop allosteric modulators of the 5-HT2CR to generate novel, highly selective and potent 5-HT2CR ligands that will act as small molecule probes for the nervous system and novel therapeutics for CNS disorders. To accomplish this objective, we plan to pursue the following two specific aims: 1) Chemical synthesis and optimization of small molecules based on PNU-69176E as the chemical lead;and 2) Biological characterization of newly synthesized compounds using a cell-based signaling assay to identify allosteric modulators of 5-HT2CR with high potency, selectivity and better drug-like properties. This project is innovative, potentially high impact research that will aid in elucidating information about the chemical neurobiology of allosteric modulation of 5-HT2CR. Our results are expected to provide the valuable SAR and novel mechanistic insight into these chemically unique allosteric modulators of 5-HT2CR.The proposed studies will identify small molecules that will be utilized to probe the neurobiology of the 5-HT2CR. The long term goal of this project is to develop these modulators for preclinical validation and clinical application in translational research and ultimately as novel therapeutic candidates.

Public Health Relevance

This research project is highly relevant to public health because it entails chemical synthesis, optimization and pharmacological investigation of novel allosteric modulators of the 5-HT2C receptor that will act as small molecule probes for nervous system and novel therapeutics for a variety of CNS disorders of significant unmet medical need. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing new medications and fundamental knowledge that will help to lengthen life and to reduce the burdens of illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH093844-02
Application #
8429363
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Driscoll, Jamie
Project Start
2012-02-17
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$220,320
Indirect Cost
$76,320
Name
University of Texas Medical Br Galveston
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Chen, Haijun; Zhou, Xiaobin; Wang, Ailan et al. (2015) Evolutions in fragment-based drug design: the deconstruction-reconstruction approach. Drug Discov Today 20:105-13
Chen, Haijun; Mrazek, Amy A; Wang, Xiaofu et al. (2014) Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Bioorg Med Chem 22:3393-404
Chen, Haijun; Yang, Zhengduo; Ding, Chunyong et al. (2014) Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3). Eur J Med Chem 82:195-203
Ding, Chunyong; Wang, Lili; Chen, Haijun et al. (2014) ent-Kaurane-based regio- and stereoselective inverse electron demand hetero-Diels-Alder reactions: synthesis of dihydropyran-fused diterpenoids. Org Biomol Chem 12:8442-52
Ye, Na; Ding, Ye; Wild, Christopher et al. (2014) Small molecule inhibitors targeting activator protein 1 (AP-1). J Med Chem 57:6930-48
Chen, Haijun; Gao, Yu; Wu, Jianlei et al. (2014) Exploring therapeutic potentials of baicalin and its aglycone baicalein for hematological malignancies. Cancer Lett 354:5-11
Chen, Haijun; He, Guihua; Li, Cailong et al. (2014) Development of a Concise Synthetic Approach to Access Oroxin A. RSC Adv 4:45151-45154
Bohanon, Fredrick J; Wang, Xiaofu; Ding, Chunyong et al. (2014) Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis. J Surg Res 190:55-63
Chen, Haijun; Wild, Christopher; Zhou, Xiaobin et al. (2014) Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC). J Med Chem 57:3651-65
Chen, Haijun; Tsalkova, Tamara; Chepurny, Oleg G et al. (2013) Identification and characterization of small molecules as potent and specific EPAC2 antagonists. J Med Chem 56:952-62

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