The central goal of this project is to synthesize novel methylphenidate analogs and evaluate their potential as medications for the treatment of cocaine addiction and as precursors to novel neuroimaging agents. Even though a reasonably wide range of methylphenidate analogs have been explored in the past, a major shortcoming with the previous studies in this area was the limitations associated with the traditional method used for the synthesis of these analogs. Having developed a very powerful two-step asymmetric synthesis of threo-methylphenidate, this enabling technology will be used for the synthesis of a wide array of methylphenidate analogs. The specific synthetic targets of the project are the following: naphthyl analogs of threo- and erythro-methylphenidate, heterocyclic analogs of threo-methylphenidate, oxa and carba analogs of threo-methylphenidate, piperidine ring-modified analogs, and polycyclic derivatives. All compounds will be initially screened for their binding to the dopamine, serotonin and norepinephrine transporters. Classes of compounds that display interesting biological properties will be extended into a more extensive series. Further in vitro and in vivo evaluation of promising compounds will be conducted. Initial studies will also be carried out to determine if useful PET radioligands can be made from any potent and selective analogs that are discovered during these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015225-02
Application #
6623128
Study Section
Special Emphasis Panel (ZRG1-SSS-P (01))
Program Officer
Biswas, Jamie
Project Start
2002-04-15
Project End
2007-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
2
Fiscal Year
2003
Total Cost
$304,390
Indirect Cost
Name
State University of New York at Buffalo
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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Davies, Huw M L; Manning, James R (2008) Catalytic C-H functionalization by metal carbenoid and nitrenoid insertion. Nature 451:417-24
Reddy, Ravisekhara P; Davies, Huw M L (2007) Asymmetric synthesis of tropanes by rhodium-catalyzed [4 + 3] cycloaddition. J Am Chem Soc 129:10312-3
Davies, Huw M L; Hedley, Simon J (2007) Intermolecular reactions of electron-rich heterocycles with copper and rhodium carbenoids. Chem Soc Rev 36:1109-19
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Davies, Huw M L; Ni, Aiwu (2006) Enantioselective synthesis of beta-amino esters and its application to the synthesis of the enantiomers of the antidepressant Venlafaxine. Chem Commun (Camb) :3110-2
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Davies, Huw M L; Walji, Abbas M (2003) Asymmetric intermolecular C-H activation, using immobilized dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)- prolinate) as a recoverable catalyst. Org Lett 5:479-82