In the previous funding period, the first small-molecule positive modulators of the GABAB receptor were discovered, and positive modulation was found to be a viable strategy for reversing behaviors with relevance to nicotine dependence in animal models, while minimizing undesired side-effects. With this application, we seek the resources to continue the development of GABA{B} receptor positive modulators and learn more about their mechanism of action. The goals of Project 1 are to complete the refinement of the existing pyrimidine-based compounds and to find alternative structures with even better properties. Guided by a detailed structure-activity study, modifications certain key positions of the pyrimidine structure are proposed to increase solubility while retaining affinity. We will also mount a parallel effort to generate new lead structures by replacing the central pyrimidine ring with heterocycles that display functional groups in similar orientations. In all cases, the synthetic routes are short, high-yielding, and tolerant of diverse functionality, in order to make it easy to optimize lead structures. Two additional lines of discovery will also be pursued. The first takes advantage of the large compound collection at Scripps Florida, which will be mined by similarity modeling to successful positive modulator structures in Project 2. The resulting candidates will be screened and new leads will be incorporated into the synthesis and testing cycle of Project 1. In addition, we will employ the technique of target-guided synthesis to convert the positive modulators already developed in this program into two-site binders to the GABA{B} receptor. This approach uses a highly selective connecting reaction to join small molecules only when simultaneously bound to adjacent sites on the target protein, giving rise to bivalent ligands of high affinity and selectivity. All new compounds will be screened by a receptor binding assay in the Finn laboratory and by second messenger and signaling assays in Project 2. By close collaboration with the in vitro testing, in vivo pharmacology, and bioinformatics capabilities of Project 2, the best compounds will be identified and refined to arrive at optimized structures for behavioral studies in animal models of nicotine dependence in Project 3.

Public Health Relevance

Tobacco smoking, attributed to the addictive properties of nicotine, is a worldwide health problem. This project will develop new agents to combat nicotine dependence by a novel mechanism. Preclinical proof of concept in these animal models may lead to the clinical development of compounds for the therapeutic indication of nicotine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19DA026838-09
Application #
8485560
Study Section
Special Emphasis Panel (ZMH1-ERB-C)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$464,208
Indirect Cost
$41,712
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
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:
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
Stoker, Astrid K; Markou, Athina (2013) Unraveling the neurobiology of nicotine dependence using genetically engineered mice. Curr Opin Neurobiol 23:493-9
Vlachou, Styliani; Guery, Sebastien; Froestl, Wolfgang et al. (2011) Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats. Psychopharmacology (Berl) 215:117-28
D'Souza, Manoranjan S; Markou, Athina (2011) Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments. Addict Sci Clin Pract 6:4-16
Vlachou, Styliani; Paterson, Neil E; Guery, Sebastien et al. (2011) Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats. Eur J Pharmacol 655:52-8
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