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Investigating DAT uptake inhibitors as potential replacement therapies for cocaine
Author(s) -
Batman Angela,
Dutta Aloke,
Reith Maarten,
Beardsley Patrick M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.713.13
Subject(s) - pharmacology , dopamine , dopamine transporter , self administration , dopamine uptake inhibitors , potency , norepinephrine transporter , serotonin , reuptake inhibitor , chemistry , medicine , norepinephrine , biochemistry , in vitro , receptor , nucleus accumbens , dopaminergic
There are no approved therapies for cocaine dependence. Our objective is to develop potential replacement medications that possess the subjective effects of cocaine but with longer durations of action and the ability to reduce cocaine self administration. Cocaine blocks the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. We have reported that our lead compound, D84, a 3‐hydroxy substituted analogue of 1‐[2‐(diphenylmethoxy)ethyl]‐4‐(3‐phenylpropyl) piperazine (GBR 12935), is one of the most potent and selective inhibitors of the DAT so far disclosed [Ki's (nM): 4.05 (DAT):1274 (SERT):164 (NET)]. D84 possesses several of our target properties and here we continue its evaluation, as well as that of new analogues. D84 dose‐dependently (9.6–30.4 mg/kg) reduces cocaine self‐administration in rats. Previously undisclosed compounds, D225, D232, and D233, elevated locomotor activity for several hours, and occasioned cocaine's discriminative stimulus effects. Compound D232 was almost 10 fold more potent than D233 in this latter regard, perhaps attributable to its greater SERT potency. The results show these new GBR 12935 analogues possess features desirable for a cocaine replacement therapy. This research was supported by NIDA Grant DA012449, A. Dutta (PI).