: Recent studies have suggested that selective D3 ligands may have therapeutic potential as novel pharmacotherapy for the treatment of drug addiction. Although a number of selective D3 ligands have been reported recently, most of them have very poor solubility to be evaluated in vivo and to be developed as potentially useful therapeutic agents. Furthermore, there were no adequate in vivo functional assays for unambiguous evaluation of their functional activity of D3 ligands at D3 receptors and their functional selectivity at the other dopamine receptors. We have recently developed and validated new in vivo functional assays that can nicely distinguish between the D3 and D2 activities. Based on novel D3 ligands we previously discovered, we have designed and synthesized a set of potent, selective D3 ligands. Our long- term goal of this project is to develop potent and highly selective D3 ligands for the treatment of drug abuse. To achieve this goal, we have assembled a multidisciplinary team consisting of investigators with extensive expertise in computational drug design and medicinal chemistry, biochemical pharmacology of dopamine receptors, and in vivo behavioral pharmacology. We will carry out the following specific aims:
Aim 1. Design and synthesize new D3 ligands, based on our promising lead compounds toward achieving highly potent and selective D3 ligands with good solubility for both in vitro and in vivo studies.
Aim 2. Evaluate these new D3 ligands in a panel of in vitro receptor binding and functional assays using both the native tissues expressing respective dopamine receptors and in cell lines transfected with each of the five dopamine receptors.
Aim 3. (a) For the highly selective D3 ligands obtained from Aims 1 and 2, characterize their functional activity using our newly developed and validated in vivo assays; and b) for several of the most promising D3 ligands, evaluate their therapeutic potential as a new therapy for the treatment of drug abuse. Potent and selective D3 ligands with varying intrinsic activity not only will serve as powerful pharmacological tools to further elucidate the role of the D3 receptor in the reinforcement mechanism of drug addiction, but also may ultimately be developed as novel pharmacotherapies for drug addiction and dependence. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020669-02
Application #
7275957
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Shih, Ming L
Project Start
2006-08-10
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$570,748
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bertz, Jeremiah W; Chen, Jianyong; Woods, James H (2015) Effects of pramipexole on the acquisition of responding with opioid-conditioned reinforcement in the rat. Psychopharmacology (Berl) 232:209-21
Chen, Jianyong; Jiang, Cheng; Levant, Beth et al. (2014) Pramipexole derivatives as potent and selective dopamine D(3) receptor agonists with improved human microsomal stability. ChemMedChem 9:2653-60
Bertz, Jeremiah W; Woods, James H (2013) Acquisition of responding with a remifentanil-associated conditioned reinforcer in the rat. Psychopharmacology (Berl) 229:235-43
Koffarnus, Mikhail N; Woods, James H (2013) Individual differences in discount rate are associated with demand for self-administered cocaine, but not sucrose. Addict Biol 18:8-18
Chen, Jianyong; Levant, Beth; Wang, Shaomeng (2012) High-affinity and selective dopamine Dýýý receptor full agonists. Bioorg Med Chem Lett 22:5612-7
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Collins, Gregory T; Cunningham, Alyssa R; Chen, Jianyong et al. (2012) Effects of pramipexole on the reinforcing effectiveness of stimuli that were previously paired with cocaine reinforcement in rats. Psychopharmacology (Berl) 219:123-35
Collins, Gregory T; Truong, Yen Nhu-Thi; Levant, Beth et al. (2011) Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D3 and D2 receptor sensitivity. Psychopharmacology (Berl) 215:609-20
Johnson, Patrick S; Madden, Gregory J; Brewer, Adam T et al. (2011) Effects of acute pramipexole on preference for gambling-like schedules of reinforcement in rats. Psychopharmacology (Berl) 213:11-8

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