'Proximity frequencies' a new parameter to evaluate the profile of GABAAR modulators.

摘要: Abstract We reported the synthesis of new 8-methoxypyrazolo[1,5-a]quinazolines bearing an amide fragment at 3-position. The final compounds, as aromatic (2a-i) and 4,5-dihydro derivatives (3a-i), have been evaluated in vitro for their ability to modulate chlorine current on recombinant GABAA receptors α1β2γ2L type (expressed frog oocytes Xenopus laevis species). From electrophysiological test two groups compounds emerged: positive modulators agonist (2e, h, i 3e, h) null antagonist (2a, b, d, f, g 3a-d, g) subtype receptor. Using a set (new derivatives, known products receptor ligands from our library) we identify amino acids α+/γ− interface, which could be involved or profile, using ‘Proximity Frequencies’, namely frequencies with ligand intercepts more binding-site during molecular dynamic simulation. linear discriminant analysis (LDA) evidences that combination αVAL203- γTHR142 αTYR 160- γTYR 58 allowed collocate 70.6% agonists 72.7% antagonists respective class.