In vitro functional characterization of GABA_B receptor modulators: The emphasis of this research project is on developing novel cell-based assays suitable to determine potency of GABA_B receptor modulators, counterscreens to assess selectivity of high priority potent modulators, functional assays to elucidate in vitro pharmacology of compounds, in vitro and in vivo drug metabolism screens, and development of cheminformatic approaches for rapid hit expansion and evaluation of chemical space. GABA_B receptor modulators that are synthesized in the laboratory of Professor MG Finn (PI of TSRI La Jolla research project) will be characterized in the aforementioned assays. Compounds with appropriate in vitro potency and pharmacology will be tested for solubility, liver microsomal stability, and in vivo pharmacokinetic properties. Compounds with acceptable in vitro profiles and with adequate in vivo PK properties will be evaluated using in vivo models in Professor Athina Markou's laboratory (PI). Iterative chemical optimization will be employed and supplemented with in silico hit expansion approaches resulting in potent and selective GABA_B modulators.

Public Health Relevance

Tobacco smoking leads to several hundred thousand deaths per year in the USA alone. The research proposed here is to discover and develop novel chemical entities for GABA_B receptors. These compounds will eventually become drug candidates for the treatment of nicotine dependence, and potentially other drug addictions.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZMH1-ERB-C)
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University of California San Diego
La Jolla
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D'Souza, Manoranjan S; Markou, Athina (2013) The "stop" and "go" of nicotine dependence: role of GABA and glutamate. Cold Spring Harb Perspect Med 3:
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Wager-Smith, Karen; Markou, Athina (2011) Depression: a repair response to stress-induced neuronal microdamage that can grade into a chronic neuroinflammatory condition? Neurosci Biobehav Rev 35:742-64