The objectives of Project 2 are the refinement and application of G protein-dependent cell-based functional assays for monitoring Orexin 1 receptor (0X1R) activity, suitable to determine potency and mechanism of action of 0X1R antagonists that have the potential to be developed as novel therapeutics for the treatment of nicotine dependence. In addition, a series of G protein-independent cell-based functional assays will be developed and optimized to further characterize 0X1R ligands and allow for identification of compounds exhibiting 'functional selectivity'. Compounds synthesized in Project 1 and compounds emerging from the OXIR high throughput screening (HTS) campaign of the 'Molecular Libraries Probe Production Centers Network'(MLPCN) sample collection will be characterized in the aforementioned assays against recombinant 0X1R in high throughput fashion. Counterscreens to assess selectivity of high priority potent modulators will also be developed and activity of interesting compounds will be confirmed using primary neuronal cells to help bridge the gap between in vitro and in vivo pharmacology. This multiple assay approach together with pharmacokinetic data generated in Project 3 is designed to drive an iterative medicinal chemistry program (Project 1) aimed at identifying potent, selective, cell penetrant 0X1R antagonists that will advance to in vivo efficacy studies in animal models of nicotine dependence (Project 4).
; Nicotine dependence is characterized by high rates of relapse to cigarette smoking during periods of abstinence. Indeed high rates of relapse are considered the greatest obstacle to successfully treating nicotine addiction. Thus, development of novel pharmacotherapeutics that can decrease the vulnerability to relapse and thereby facilitate long-term abstinence is crucial for effective treatment of nicotine dependence.
| Wall, Teagan R; Henderson, Brandon J; Voren, George et al. (2017) TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors. Front Pharmacol 8:641 |
| Patouret, Remi; Kamenecka, Theodore M (2016) Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction. Tetrahedron Lett 57:1597-1599 |
| Doebelin, Christelle; He, Yuanjun; Kamenecka, Theodore M (2016) Multigram-scale Synthesis of Enantiopure 3,3-Difluoroproline. Tetrahedron Lett 57:5658-5660 |
| 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 |
| Jiang, Rong; Song, Xinyi; Bali, Purva et al. (2012) Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists. Bioorg Med Chem Lett 22:3890-4 |
| Harmey, Dympna; Griffin, Patrick R; Kenny, Paul J (2012) Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions. Nicotine Tob Res 14:1300-18 |
