There is currently no pharmacotherapy for cocaine abuse. This public health crisis is addressed in this application that is directly responsive to RFA-DA-07-006. This application is for development of novel serotonin 5HT2C receptor agonist drugs with 5HT2A/5HT2B receptor antagonist activity to attenuate the behavioral and neurochemical effects of cocaine use and dependence. Preclinical data indicate activation of brain 5HT2C receptors attenuates the reinforcing effects of cocaine, whereas discriminative stimulus and reinstating effects of cocaine are sensitive to attenuation by both 5HT2C activation and 5HT2A blockade. Meanwhile, activation of brain 5HT2A receptors produces psychotomimetic effects and activation of peripheral 5HT2B receptors produces cardiac valvulopathy and pulmonary hypertension. Currently, there is no 5HT2C receptor agonist reported that does not also activate 5HT2A and/or 5HT2B receptors. Preliminary Data reported here, however, demonstrate that a molecule synthesized in our lab, (1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), is a full-efficacy agonist at human 5HT2C receptors, plus, an antagonist at 5HT2A and 5HT2B receptors. This dual activity (activation/blockade) at multiple serotonin receptors is unique to (-)-trans-PAT and is hypothesized to provide pharmacological treatment for cocaine addiction without cardiotoxicity. Innovative approaches include targeted syntheses of novel PAT-type stereoprobes to map 3D molecular determinants for selective activation of 5HT2C receptors and sophisticated self-administration procedures to identify cocaine's abuse-related effects that are sensitive to modulation by PAT analogs. Microdialysis with capillary electrophoresis/ laser-induced fluorescence will allow 15-sec temporal resolution of neurochemical changes in cocaine self-administering rats to identify neurochemical mechanisms of PAT therapeutic effects.
The Specific Aims are: (1) PAT analog syntheses and quantitative structure-activity relationship modeling, (2) in vitro characterization of PAT 5HT2 affinity and functional activity, (3) in vivo behavioral pharmacology studies to evaluate PAT modulation of the abuse-related effects of cocaine, and (4) in vivo analysis of the PAT-cocaine neurochemical interactions. This research is undertaken by a multidisciplinary team of researchers for preclinical development of novel compounds that likely will translate to an innovative pharmacological intervention for cocaine abuse. ? ? ?

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZDA1-MXS-M (17))
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Shih, Ming L
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University of Florida
Schools of Pharmacy
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Sakhuja, Rajeev; Kondabolu, Krishnakanth; Córdova-Sintjago, Tania et al. (2015) Novel 4-substituted-N,N-dimethyltetrahydronaphthalen-2-amines: synthesis, affinity, and in silico docking studies at serotonin 5-HT2-type and histamine H1 G protein-coupled receptors. Bioorg Med Chem 23:1588-600
Kasper, James M; Booth, Raymond G; Peris, Joanna (2015) Serotonin-2C receptor agonists decrease potassium-stimulated GABA release in the nucleus accumbens. Synapse 69:78-85
Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan et al. (2014) Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: Receptor homology modeling, ligand docking, and molecular dynamics results validated by experimental studies. Mol Phys 112:398-407
Canal, Clinton E; Morgan, Drake; Felsing, Daniel et al. (2014) A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses. J Pharmacol Exp Ther 349:310-8
Canal, Clinton E; Cordova-Sintjago, Tania; Liu, Yue et al. (2013) Molecular pharmacology and ligand docking studies reveal a single amino acid difference between mouse and human serotonin 5-HT2A receptors that impacts behavioral translation of novel 4-phenyl-2-dimethylaminotetralin ligands. J Pharmacol Exp Ther 347:705-16
Morgan, Drake; Kondabolu, Krishnakanth; Kuipers, Allison et al. (2013) Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications. Neuropharmacology 72:274-81
Canal, Clinton E; Booth, Raymond G; Morgan, Drake (2013) Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model. Neuropharmacology 70:112-21
Kasper, James; Tikamdas, Rajiv; Kim, Myong Sang et al. (2013) The serotonin-2 receptor modulator, (-)-trans-PAT, decreases voluntary ethanol consumption in rats. Eur J Pharmacol 718:98-104
Rdova-Sintjago, Tania Có; Villa, Nancy; Canal, Clinton et al. (2012) Human Serotonin 5-HT2C G Protein-Coupled Receptor Homology Model from the ?2 Adrenoceptor Structure: Ligand Docking and Mutagenesis Studies. Int J Quantum Chem 112:
Córdova-Sintjago, Tania; Sakhuja, Rajeev; Kondabolu, Krishnakanth et al. (2012) Molecular Determinants for Ligand Binding at Serotonin 5-HT2A and 5-HT2C GPCRs: Experimental Affinity Results Analyzed by Molecular Modeling and Ligand Docking Studies. Int J Quantum Chem 112:3807-3814

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