163631-02-5Relevant articles and documents
Focus on Human Monoamine Transporter Selectivity. New Human DAT and NET Models, Experimental Validation, and SERT Affinity Exploration
Ortore, Gabriella,Orlandini, Elisabetta,Betti, Laura,Giannaccini, Gino,Mazzoni, Maria Rosa,Camodeca, Caterina,Nencetti, Susanna
, p. 3214 - 3232 (2020)
The most commonly used antidepressant drugs are the serotonin transporter inhibitors. Their effects depend strongly on the selectivity for a single monoamine transporter compared to other amine transporters or receptors, and the selectivity is roughly influenced by the spatial protein structure. Here, we provide a computational study on three human monoamine transporters, i.e., DAT, NET, and SERT. Starting from the construction of hDAT and hNET models, whose three-dimensional structure is unknown, and the prediction of the binding pose for 19 known inhibitors, 3D-QSAR models of three human transporters were built. The training set variability, which was high in structure and activity profile, was validated using a set of in-house compounds. Results concern more than one aspect. First of all, hDAT and hNET three-dimensional structures were built, validated, and compared to the hSERT one; second, the computational study highlighted the differences in binding site arrangement statistically correlated to inhibitor selectivity; third, the profiling of new inhibitors pointed out a conservation of the inhibitory activity trend between rabbit and human SERT with a difference of about 1 order of magnitude; fourth, binding and functional studies confirmed 4-(benzyloxy)-4-phenylpiperidine 20a-d and 21a-d as potent SERT inhibitors. In particular, one of the compounds (compound 20b) revealed a higher affinity for SERT than paroxetine in human platelets.
Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists
Sasmal, Sanjita,Balaji, Gade,Kanna Reddy, Hariprasada R.,Balasubrahmanyam,Srinivas, Gujjary,Kyasa, Shivakumar,Sasmal, Pradip K.,Khanna, Ish,Talwar, Rashmi,Suresh,Jadhav, Vikram P.,Muzeeb, Syed,Shashikumar, Dhanya,Harinder Reddy,Sebastian,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
scheme or table, p. 3157 - 3162 (2012/06/04)
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors
Nencetti, Susanna,Mazzoni, Maria R.,Ortore, Gabriella,Lapucci, Annalina,Giuntini, Janette,Orlandini, Elisabetta,Banti, Irene,Nuti, Elisa,Lucacchini, Antonio,Giannaccini, Gino,Rossello, Armando
experimental part, p. 825 - 834 (2011/04/18)
With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measu
