The dopamine (DA) transporter is critical to many physiological and pat logical processes. This transporter has been shown to play an important role in cocaine addiction and has been considered a suitable molecular target to monitor the progression of Parkinson's disease (PD). The primary objectives of this proposal are to develop highly specific and potent ligands for this transporter and to investigate their pharmacological profiles. Present existing ligands for this transporter suffer either from non-specificity or low affinity. In this regard, the preliminary studies from our laboratory have led to the discovery of a novel highly specific and potent ligand 4-[2-[bis(4- fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, and a ligand of low affinity 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine, 1a. Our results have demonstrated that only one nitrogen atom in the piperazine moiety of the GBR compounds and its correct location in the piperidine ring, as in our proposed compounds, are crucial for their high affinity and selectivity for the DA transporter. The results also showed that the replacement of the piperazine moiety by a piperidine ring induces a substantial reduction of the non-specific piperazine site binding in 1b. This non-specific binding exists in GBR molecules. We now propose to continue our ongoing studies and plan to design and synthesize a series of different analogs of 1b in order to optimize the structures of these analogs for the development of more potent and specific compounds. The attenuation of the affinity of these analogs for """"""""piperazine acceptor"""""""" binding sites will be addressed in our proposed compounds. The evaluation of the biological activities will be done on these analogs to determine their selectivity and potency. Ideal compounds will then be radiolabelled and detailed in vitro pharmacological profile and binding kinetics study will be carried out. The results from these studies will be compared with those from currently available probes. Autoradiographical analysis of the radiolabelled drug will be done both in MPTP treated and untreated monkey brain to explore the viability of these ligands as probes for the DA transporter and as markers in SPECT or PET studies for presymptomatic diagnosis of PD or other basal ganglia diseases. An ideal probe, which may develop from these studies, will also be able to characterize the cocaine binding sites in the primate brain to provide fundamental information on the distribution and pharmacological properties of these sites. These findings will also relate to cocaine abuse. Additionally, compounds of this type could antagonize cocaine effects as has been reported for GBR 12909. Our long term goal is to promote developments that will lead to an effective treatment of cocaine abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Wayne State University
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Schools of Pharmacy
United States
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Dutta, Aloke K; Zhang, Shijun; Kolhatkar, Rohit et al. (2003) Dopamine transporter as target for drug development of cocaine dependence medications. Eur J Pharmacol 479:93-106
Dutta, A K; Fei, X S; Vaughan, R A et al. (2001) Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label. Life Sci 68:1839-49
Vaughan, R A; Gaffaney, J D; Lever, J R et al. (2001) Dual incorporation of photoaffinity ligands on dopamine transporters implicates proximity of labeled domains. Mol Pharmacol 59:1157-64
Dutta, A K; Reith, M E; Madras, B K (2001) Synthesis and preliminary characterization of a high-affinity novel radioligand for the dopamine transporter. Synapse 39:175-81
Dutta, A K; Xu, C; Reith, M E (1998) Tolerance in the replacement of the benzhydrylic O atom in 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives by an N atom: development of new-generation potent and selective N-analogue molecules for the dopamine transporter. J Med Chem 41:3293-7
Dutta, A K; Coffey, L L; Reith, M E (1998) Potent and selective ligands for the dopamine transporter (DAT): structure-activity relationship studies of novel 4-[2-(diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine analogues. J Med Chem 41:699-705
Dutta, A K; Coffey, L L; Reith, M E (1997) Highly selective, novel analogs of 4-[2-(diphenylmethoxy)ethyl]- 1-benzylpiperidine for the dopamine transporter: effect of different aromatic substitutions on their affinity and selectivity. J Med Chem 40:35-43
Dutta, A K; Xu, C; Reith, M E (1996) Structure-activity relationship studies of novel 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: synthesis and biological evaluation at the dopamine and serotonin transporter sites. J Med Chem 39:749-56