Computer‐Aided Drug Design of (R)‐Baclofen Isoxazole and Tetrazole Derivatives: Searching for Novel GABAB Receptor Agonists

Currently, ( R )‐baclofen is the only FDA‐approved agonist of the GABA B receptor for the treatment of muscle spasticity and spinal cord injuries. However, its efficacy is limited by its low cerebral uptake and short duration, necessitating high concentrations that can lead to toxic effects. In this study, we designed new ( R )‐baclofen derivatives as potential GABA B agonists, employing three different drug design strategies. We modified the three structural elements of ( R )‐baclofen: 1) replacing the para ‐chlorophenyl with an isoxazole ring, 2) changing the carboxylic acid with a tetrazole ring, and 3) altering the amino group to increase its lipophilicity. Electronic and steric effects resulting from the isosteric replacements (isoxazole and tetrazole rings) were analyzed using natural bond orbital (NBO) and molecular electrostatic potential (MEP) surfaces analysis. A robust molecular docking technique was used to study the molecular interaction of our candidates with the GABA B receptor. To achieve this, we employed molecular dynamics simulations to generate a substantial number of conformers of the GABA B1 receptor. Our final candidates, ( R )‐ 9s , ( R )‐ 12f , ( R )‐ 13f , ( R )‐ 14a , and ( R )‐ 14b , exhibited higher lipophilicity (ClogP) and interaction energies (kcal/mol) than ( R )‐baclofen and other known GABA B receptor agonists, thereby enhancing their ADME properties, including permeability across the blood–brain barrier.