The Translational Addiction Sciences Center (TASC) is focused on understanding the role of disrupted serotonin (5-HT) signaling through the 5-HT2A receptor (S-HTZAR) and 5-HT2cR in relapse precipitated by impulsive behavior and craving in the face of cocaine-associated cues (cue reactivity). The mechanisms and neural circuitry through which the 5-HT2AR:5-HT2CR balance controls these behaviors are being explored in Projects 1 and 2, and accumulating data indicate that strategies incorporating combined 5- HT2AR antagonist/5-HT2cR agonist properties will prove particularly effective to suppress impulsivity and cue reactivity and reduce relapse. We have recently demonstrated for the first time that a 5-HT2A+2CR heteromer is found in vitro and ex vivo. These intriguing data raise the wholly-original possibility that these two receptors may directly dimerize and exhibit biochemical properties that are demonstrably distinct from those of its individual components. To explore these hypotheses, new pharmacological tools are required to study the role of 5-HT2AR:5-HT2CR signaling and to elucidate the potential functional impact of 5-HT2R dimerization. Our primary objectives are to develop novel molecules which (1) possess dual activity as a 5-HT2AR antagonist and S-HTacR agonist, and (2) enable structural and functional analyses of 5-HT2R dimerization. Project 3 is taking the novel approach of designing and synthesizing a 5-HT2AR antagonist tethered to a 5-HT2cR agonist; there have been very few cases in which different receptor ligands have been tethered together in an attempt to stimulate one receptor while blocking the other. The molecules synthesized in this Project will be used to study the biology of these proteins and will have the ability to bind to specific dimeric receptors and alter their effector pathways selectively (Project 2, Core B). Biotinylated and fluorescently-labeled molecules will also be synthesized to visualize the location and formation of receptor dimers in vitro and ex vivo. In addition to synthesizing selective bivalent ligands at the bench, an in vivo synthetic approach, using reactions templated by receptor dimers, will be developed to probe receptor dimerization and provide novel, new bivalent ligands. Achievement of these Aims will provide us with novel and innovative pharmacological tools necessary to conduct detailed analyses of the impact of 5-HT2A+2CR heterodimerization on the balance of 5-HT2R function, and to test the overarching hypothesis that pharmacological restoration of 5-HT2AR:5-HT2CR balance will minimize deleterious behaviors that promote relapse in cocaine dependence. R E L E V A N C E (See instructions): The need for new tools and proof-of-principle for therapeutics development is vitally translational and we will direct these efforts toward the creation of targeted serotonergic molecules with fundamentally new mechanisms of action for treatment of cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
4P50DA033935-04
Application #
9058513
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Gilbertson, Scott R; Chen, Ying-Chu; Soto, Claudia A et al. (2018) Synthesis and activity of functionalizable derivatives of the serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907. Bioorg Med Chem Lett 28:1381-1385
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Chen, Ying-Chu; Hartley, Rachel M; Anastasio, Noelle C et al. (2017) Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT2C Receptor Agonist. ACS Chem Neurosci 8:1004-1010
Bjork, James M; Burroughs, Thomas K; Franke, Laura M et al. (2017) Rapid-Response Impulsivity Predicts Depression and Posttraumatic Stress Disorder Symptomatology at 1-Year Follow-Up in Blast-Exposed Service Members. Arch Phys Med Rehabil 98:1646-1651.e1
Ahn, Woo-Young; Ramesh, Divya; Moeller, Frederick Gerard et al. (2016) Utility of Machine-Learning Approaches to Identify Behavioral Markers for Substance Use Disorders: Impulsivity Dimensions as Predictors of Current Cocaine Dependence. Front Psychiatry 7:34

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