Background: Second generation or “atypical” antipsychotics demonstrate an improved
therapeutic profile over conventional neuroleptics. These are effective in both positive and negative
symptoms of the disease and have a lower propensity to induce adverse symptoms.
Objective: The main objective of the research was in silico design and synthesis of potential atypical
antipsychotics with combined antiserotonergic / antidopaminergic effect.
Methods: A one pot synthesis of aryl substituted imidazole derivatives was carried out in green
solvent PEG-400 and the prepared compounds were evaluated for atypical antipsychotic activity in
animal models for dopaminergic and serotonergic antagonism. The compounds were designed
based on their 3D similarity studies to standard drugs and in silico (docking studies) with respect to
Results: Results from the docking studies with respect to 5-HT2A
receptors suggested a potential
atypical antipsychotic profile for the test compounds. Theoretical ADME profiling of the
compounds based on selected physicochemical parameters suggested an excellent compliance with
Lipinski’s rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was
computed through an online software program and the values obtained for the compounds suggested
a good potential for brain permeation. Reversal of apomorphine induced mesh climbing behaviour
coupled with inactivity in the stereotypy assay indicates antidopaminergic effect and a potential
atypical profile for the test compounds 1-5. Further, the activity of compounds in DOI assay
indicated a 5-HT2
antagonistic profile (5-HT2
Conclusion: Compound 5 emerged as important lead compound showing combined antidopaminergic
and antiserotonergic (5-HT2A
) activity with a potential atypical antipsychotic profile.