Background: Sulpiride, which has selective dopaminergic blocking activity, is a substituted
benzamide antipsychotic drug playing a prominent role in the treatment of schizophrenia,
which more selective and primarily blocks dopamine D2 and D3 receptor.
Objective: This study has two main objectives, firstly; the molecular modeling studies (MD and
Docking, ADME) were conducted to define the molecular profile of sulpiride and sulpiridereceptor
interactions, another to synthesize polymeric nanoparticles with chitosan, having the advantage
of slow/controlled drug release, to improve drug solubility and stability, to enhance utility
and reduce toxicity.
Methods: Molecular dynamic simulation was carried out to determine the conformational change
and stability (in water) of the drug and the binding profile of D3 dopamine receptor was determined
by molecular docking calculations. The pharmacological properties of the drug were revealed by
ADME analysis. The ionic gelation method was used to prepare sulpiride loaded chitosan nanoparticles
(CS NPs). The Dynamic Light Scattering (DLS), UV-vis absorption (UV), Scanning Electron
Microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy techniques were carried out to
characterize the nanoparticles. In vitro cell cytotoxicity experiments examined with MTT assay on
mouse fibroblast (L929), human neuroblastoma (SH-SY5Y) and glioblastoma cells (U-87). The statistical
evaluations were produced by ANOVA.
Results: The residues (ASP-119, PHE-417) of D3 receptor provided a stable docking with the drug,
and the important pharmacological values (blood brain barrier, Caco-2 permeability and human oral
absorption) were also determined. The average particle size, PdI and zeta potential value of sulpiride-
loaded chitosan NPs having a spherical morphology were calculated as 96.93 nm, 0.202 and
+7.91 mV. The NPs with 92.8% encapsulation and 28% loading efficiency were found as a slow
release profile with 38.49% at the end of the 10th day. Due to the formation of encapsulation, the
prominent shifted wave numbers for C-O, S-O, S-N stretching, S-N-H bending of Sulpiride were
also identified. Mitochondrial activity of U87, SHSY-5Y and L929 cell line were assayed and evaluated
using the SPSS program.
Conclusion: To provide more efficient use of Sulpiride having a low bioavailability of the gastrointestinal
tract, the nanoparticle formulation with high solubility and bioavailability was designed and
synthesized for the first time in this study for the treatment of schizophrenia. In addition to all
pharmacological properties of drug, the dopamine blocking activity was also revealed. The toxic
effect on different cell lines have also been interpreted.