The present study was focused on MM-GBSA and MM-PBSA model performance in activity evaluation of AMPA receptor pos. allosteric modulators with the dimer of ligand-binding domains of the GluA2 receptor.The largest data-set was obtained using FLIPR methodol., affinity was also measured by radio-labeled ligand substitution method and their statistical anal. was performed in R 3.0.2, plots were made with ggplot2 package.The results showed significance level of the number of rotatable bonds in MM-GBSA-based model is quite low, at the same time, the model created using MM-GBSA and the number of bound ligands demonstrates the significance of the latter variable and interestingly, a variable ′the number of rotatable bonds′ becomes significant in MM-PBSA-based model and allows one to increase R² up to 0.70 but the sign of ′nrot′ coefficient is pos. which is not consistent with the theor. sign of entropy contribution.The author concluded that both GBSA and PBSA solvation models showed good performance for the described data-set and demonstrated that AMBER14 binding energy reasonably correlated with pEC50 for AMPA receptor pos. allosteric modulators.

01 Mar 2017·British Journal of Pharmacology

Pharmacological characterization of N‐[(2S)‐5‐(6‐fluoro‐3‐pyridinyl)‐2, 3‐dihydro‐1H‐inden‐2‐yl]‐2‐propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator

Article

Author: Gartlon, Jane ; Dawson, Lee A ; Calcinaghi, Novella ; Selina Mok, M H ; Jones, Declan N C ; Harries, Mark H ; Starr, Kathryn ; Pardoe, Joanne ; Ward, Simon E ; Oliosi, Beatrice ; Lacroix, Laurent ; Woolley, Marie L ; Graziani, Francesca ; Beswick, Paul

Background and PurposeAMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application.Experimental Approach[N‐[(2S)‐5‐(6‐fluoro‐3‐pyridinyl)‐2,3‐dihydro 1H–inden‐2‐yl]‐2‐propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent.Key ResultsWe demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero‐oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor‐mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay‐induced deficit in novel object recognition in rats after both acute and sub‐chronic dosing. Sub‐chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg−1. UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine‐impaired rats and water maze learning and retention in aged rats. In side‐effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg−1.Conclusion and ImplicationsWe conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.

01 Feb 2016·Russian Chemical Bulletin

Pharmacophore analysis of positive allosteric modulators of AMPA receptors

Author: N. S. Zefirov ; M. I. Lavrov ; D. S. Karlov ; V. A. Palyulin

A 3D QSAR study of a set of pos. allosteric modulators of AMPA receptors was performed using the CoMFA approach.It was shown that the van der Waals component introduces the major contribution to the predicted pEC₅₀ values, while the contribution of the electrostatic component is minor.The pharmacophore hypothesis for pos. allosteric modulators was generated and validated.

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Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Phase 1	-	GSK Plc	-

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