Immediate therapies are needed for the treatment of cocaine abuse worldwide. In this direction, we recently identified a piperidne-based analog of cocaine (specifically, the trans isomer of 1-methyl-4-(4-chlorophenyl) piperdine-3-carboxylic acid methyl ester) that binds to the cocaine recognition site with comparable affinity to cocaine; additionally, this compound acts as an inhibitor of dopamine uptake. In spite of the compound's potency, it has been observed that in discrimination studies in rats, the compound exhibits only weak cocaine-amphetamine-like effects. Unlike cocaine, this compound has weak motor stimulant effects and is not self administered by rats. These results appear to be promising from the standpoint of discovering a possible medication for drug abuse treatment. In order to properly follow up on these encouraging preliminary results, the investigators plan to conduct further chemical analog synthesis, in vitro pharmacological studies, and in vivo animal experiments on the 4-phenylpiperidine analogs with the objective to improve upon the biological profile of this compound. Within the context of this proposal, it is our intention to pursue the following specific aims: 1. To conduct additional structure-activity relationship studies in order to establish that they are advancing the best compound(s) as possible medications. These studies would include preparation of the lead structure in optically pure form, and the design and synthesis of related analogs embodying a the following structural changes: a) modification of the nature and position of the substituent borne by phenyl ring; b) replacement of the N-methyl group by other alkyl groups and sulfonyl groups, as well as isosteric replacement of NMe by CH2 and O; c) replacemnt of the ester group by alkyl and alkenyl groups. 2. To characterize all newly synthesized analogs pahamacologically in in vitro binding experiments, and for the inhibition of the 5HT, NE, and DA uptake. 3. For selected compounds, to evaluate the intravenous safety of the candidate compounds, and for compounds meeting the saftey critieria, to carry out locomotion activity assays. 4. For compounds meeting set criteria, to further evaluate their behavioral pharmacological profile in animals using intravenous drug self-administration and drug discrimination procedures.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA011548-01
Application #
2467371
Study Section
Special Emphasis Panel (ZDA1-KXN-G (20))
Project Start
1997-09-30
Project End
2002-07-31
Budget Start
1997-09-30
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Georgetown University
Department
Neurology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Zhou, Jia; Klass, Thomas; Johnson, Kenneth M et al. (2005) Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants. Bioorg Med Chem Lett 15:2461-5
Petukhov, Pavel A; Zhang, Jianrong; Wang, Cheng Z et al. (2004) Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring. J Med Chem 47:3009-18
Zhou, Jia; He, Rong; Johnson, Kenneth M et al. (2004) Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. J Med Chem 47:5821-4
Zhou, Jia; Zhang, Ao; Klass, Thomas et al. (2003) Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites. J Med Chem 46:1997-2007
Zhou, Jia; Klass, Thomas; Zhang, Ao et al. (2003) Synthesis and pharmacological evaluation of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes: thiophene analogues as potent norepinephrine transporter inhibitors. Bioorg Med Chem Lett 13:3565-9
Zhang, Ao; Zhou, Guochun; Rong, Suo-Bao et al. (2002) Thiophene derivatives: a new series of potent norepinephrine and serotonin reuptake inhibitors. Bioorg Med Chem Lett 12:993-5
Woolverton, W L; Ranaldi, R; Wang, Z et al. (2002) Reinforcing strength of a novel dopamine transporter ligand: pharmacodynamic and pharmacokinetic mechanisms. J Pharmacol Exp Ther 303:211-7
Zhang, Ao; Zhou, Guochun; Hoepping, Alexander et al. (2002) Further studies on conformationally constrained tricyclic tropane analogues and their uptake inhibition at monoamine transporter sites: synthesis of (Z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes as a novel class of serotonin transpo J Med Chem 45:1930-41
Petukhov, Pavel A; Zhang, Jianrong; Kozikowski, Alan P et al. (2002) SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement. J Med Chem 45:3161-70
Trzcinska, M; Pimentel, P; Stellar, J R et al. (2001) Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward. Pharmacol Biochem Behav 68:171-80

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