IN VITRO AND IN SILICO SCREENING OF 6-FLUORO-3-(PIPERIDIN-4-YL) BENZO[D]ISOXAZOLE DERIVATIVES FOR BLOOD BRAIN BARRIER PERMEABILITY

Abstract

Blood Brian Barrier (BBB) is a physiologically and metabolically significant membrane that enables and limits the uptake of specific molecules by the brain, thus preserving the homeostasis within the Central nervous System (CNS).All the Antipsychotic drugs are permeable across the BBB, however most of First/Second generation antipsychotic drugs employed in the medical field are known to be associated with Extrapyramidal symptoms (EPS). Hence our interest is devoted in the development of novel antipsychotic drugs that ameliorate psychosis with least frequency of EPS. In our previous study the newly synthesized molecules, 6-fluoro-3-(piperidin-4-yl) benzo[d]isoxazole derivatives (S1-S4) which have shown positive alterations in chemical properties and biological activities demonstrating significant neuroleptic properties. However possibility and efficiency of these synthesized molecules to penetrate through the Blood Brain Barrier will be of utmost importance to determine its treatment efficacy. In this line of investigation, in the present study, in silico and in vitro methods are employed to evaluate the permeability in comparison with that of standard antipsychotic drugs, Resperidone and Haloperidol. In vitro analysis was done by Parallel artificial Membrane Permeability Assay (PAMPA) in PBS, where in permeability of S2(8.3x10^-6) and S3(6.6x10^-6) molecules showed higher permeability than known standards Warfarin(1x10^-6), Resperidone(2.3x10^-6) and Haloperidol(3.5x10^-6), and the molecules exhibited recovery above 50% and in silico studies also showed high permeability rate with all the synthesized molecules. Thus we can conclude that, all the synthesized molecules have the potential to develop into promising Antipsychotic drugs.

Key words: Antipsychotics, Blood Brain Barrier, EPS, PAMPA, In silico