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.
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