Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.
Article Details
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Houlihan WJ, Ahmad UF, Koletar J, Kelly L, Brand L, Kopajtic TA
Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.
J Med Chem. 2002 Sep 12;45(19):4110-8.
- PubMed ID
- 12213054 [ View in PubMed]
- Abstract
A series of mazindol (1), homomazindol (2), and bishomomazindol (3) derivatives with a benzo or cyclohexano ring fused at various sites were prepared as part of an SAR study to determine the effect of increased aliphatic and aromatic lipophilicity on selected in vitro assays used to identify potential cocaine-like and cocaine antagonism activity. Very good (IC(50) = 2-3 nM) inhibition of [(3)H] WIN 35,428 and [(125)I] RTI-55 binding on rat or guinea pig striatal membranes and HEK cells expressing cDNA for the human dopamine transporter (HEK-hDAT) was shown by the 8,9-benzomazindol 25 and 9,10-benzohomomazindol 28. All new compounds were weaker inhibitors of [(3)H] DA uptake in HEK-hDAT cells than 1 and 2. No improvement in the binding selectivity ratio (SERT/DAT and NET/DAT) was found when compared to 2. Compounds 25and 28 showed a considerable increase versus 1 in uptake/binding discrimination ratios at the DAT (311.0 and 182.1 vs 0.9), SERT (33.6 and 127.3 vs 1.9), and NET (7.3 and 10.0 vs 0.3).
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Mazindol Sodium-dependent dopamine transporter Ki (nM) 45 N/A N/A Details Mazindol Sodium-dependent dopamine transporter IC 50 (nM) 42.6 N/A N/A Details Mazindol Sodium-dependent noradrenaline transporter Ki (nM) 18 N/A N/A Details Mazindol Sodium-dependent serotonin transporter Ki (nM) 50 N/A N/A Details