Background: Nipecotic acid is considered to be one of the most potent inhibitors of
neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro. However, nipecotic acid does not
readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its
Objective: A series of substituted acetonaphthones tethered nipecotic acid derivatives were
designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier
Methods: Synthesized compounds were tested in mice models of PTZ, pilocarpine, and DMCM
induced epilepsy, in vivo. The rota-rod test was performed to determine the acute neurotoxicity of
the potential leads (4a, 4b, and 4i). These potential hybrids were also evaluated for their ability to
cross the BBB by an in vitro parallel artificial membrane permeability BBB assay (PAMPA-BBB).
The leads were subjected to in silico molecular docking and dynamics studies on homology
modelled protein of human GABA (γ-amino butyric acid) transporter 1 (GAT1) and prediction of
their pharmacokinetic properties.
Result: Amongst the synthesized derivatives, compounds 3a, 3b, 3i, 4a, 4b, and 4i exhibited
increased latency of seizures against subcutaneous pentylenetetrazole (scPTZ) induced seizures in
mice. Derivatives 4a, 4b, 4i were more effective compared to nipecotic acid ester counterparts 3a,
3b and 3i placing the importance of the presence of free carboxyl group in the centre. The findings
revealed that 4i was comparatively more permeable (Pe= 8.89) across BBB than the standard
tiagabine (Pe= 7.86). In silico studies proved the consensual interactions of compound 4i with the
active binding pocket.
Conclusion: Some nipecotic acid-acetonaphthone hybrids with considerable anti-epileptic activity,
drug like properties and the ability to permeate the BBB have been successfully synthesized.