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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Robinson, James D; McDonald, Patricia H (2015) The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism. Cell Signal 27:1449-56
Li, Xia; Kaczanowska, Katarzyna; Finn, M G et al. (2015) The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats. Neuropharmacology 97:357-64
Li, Xia; Semenova, Svetlana; D'Souza, Manoranjan S et al. (2014) Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation. Neuropharmacology 76 Pt B:554-65
Stoker, Astrid K; Markou, Athina (2013) Unraveling the neurobiology of nicotine dependence using genetically engineered mice. Curr Opin Neurobiol 23:493-9
Chirapu, Srinivas Reddy; Rotter, Charles J; Miller, Emily L et al. (2013) High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid. Curr Top Med Chem 13:837-42
Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea et al. (2013) Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice. Neuropharmacology 70:156-67
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:
Canny, Stephanie A; Cruz, Yasel; Southern, Mark R et al. (2012) PubChem promiscuity: a web resource for gathering compound promiscuity data from PubChem. Bioinformatics 28:140-1
D'Souza, Manoranjan S; Markou, Athina (2012) Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. Neuropharmacology 62:1564-73
Southern, Mark R; Griffin, Patrick R (2011) A Java API for working with PubChem datasets. Bioinformatics 27:741-2

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