A novel binding assay identifies high affinity ligands to the rosiglitazone binding site of mitoNEET.
Binding Sites/drug effects; Dose-Response Relationship; Drug; Ligands; Mitochondrial Proteins/*antagonists & inhibitors/metabolism; Molecular Structure; Recombinant Proteins/antagonists & inhibitors/metabolism; Rosiglitazone; Stereoisomerism; Structure-Activity Relationship; Thiazolidinediones/chemical synthesis/chemistry/*pharmacology
A novel outer mitochondrial membrane protein containing [2Fe-2S] clusters, mitoNEET was first identified through its binding to the anti-diabetic drug pioglitazone. Pioglitazone belongs to a family of drugs that are peroxisome proliferator-activated receptor (PPAR) gamma agonists, collectively known as glitazones. With the lack of pharmacological tools available to fully elucidate mitoNEET's function, we developed a binding assay to probe the glitazone binding site with the aim of developing selective and high affinity compounds. We used multiple thiazolidine-2,4-dione (TZD), 2-thioxothiazolidin-4-one (TTD), and
Geldenhuys Werner J; Funk Max O; Awale Prabha S; Lin Li; Carroll Richard T
Bioorganic & medicinal chemistry letters
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2011.06.111" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2011.06.111</a>
Structure-activity relationship and docking studies of thiazolidinedione-type compounds with monoamine oxidase B.
Animals; Humans; Inbred C57BL; Male; Mice; Models; Molecular; Molecular Structure; Monoamine Oxidase Inhibitors/chemical synthesis/chemistry/*pharmacology; Monoamine Oxidase/*metabolism; Stereoisomerism; Structure-Activity Relationship; Thiazolidinediones/chemical synthesis/chemistry/*pharmacology
The neuroprotective activity of pioglitazone and rosiglitazone in the MPTP parkinsonian mouse prompted us to evaluate a set of thiazolidinedione (TZD) type compounds for monoamine oxidase A and B inhibition activity. These compounds were able to inhibit MAO-B over several log units of magnitude (82 nM to 600 muM). Initial structure-activity relationship studies identified key areas to modify the aromatic substituted TZD compounds. Primarily, substitutions on the aromatic group and the TZD nitrogen were key areas where activity was enhanced within this group of compounds.
Carroll Richard T; Dluzen Dean E; Stinnett Hilary; Awale Prabha S; Funk Max O; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2011.06.060" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2011.06.060</a>
Temporal differences in behavioral effect of fenfluramine and norfenfluramine.
Male; Animals; Rats; Behavior; Stereoisomerism; Injections; Discrimination Learning/*drug effects; Fenfluramine/*analogs & derivatives/*pharmacology; Norfenfluramine/*pharmacology; Dose-Response Relationship; Drug; Inbred Strains; Intraperitoneal; Animal/*drug effects
Ten male rats were trained to discriminate the anorectic drug d,l-fenfluramine (2.0 mg/kg intraperitoneally administered) from its vehicle using a food-reinforced (fixed-ratio 10 schedule) two-lever operant task. Once learned, the fenfluramine stimulus was dose-dependent (ED50 = 0.8 mg/kg) and stereoselective with the d-isomer (ED50 = 0.6 mg/kg) approximate twice as potent as the l-isomer (ED50 = 1.2 mg/kg). Time-course data indicate that the fenfluramine metabolite norfenfluramine produces a significantly faster onset and longer duration of action than does the parent compound. The results suggest that both stereoisomers of fenfluramine have discriminative stimulus properties and that the fenfluramine metabolite, norfenfluramine, contributes to the discriminative stimulus properties of the parent drug.
Schechter M D
Pharmacology, biochemistry, and behavior
1990
1990-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(90)90284-o" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(90)90284-o</a>