3‐ and 5‐Isoxazolol zwitterions: A model of interaction with the GABA‐A receptor relating to agonism and antagonism

Using molecular orbital methods, we propose various models of interactions between GABA or analogs (TACA, muscimol, isomuscimol) and an hypothetical receptor molecular fragment, a methylguanidinium ion. The respective geometries of the GABA‐, TACA‐, muscimol‐, and isomuscimol–methylguanidinium ion complexes are optimized using the semi‐empirical MNDO method. Stabilization energies of the complexes obtained by substraction of the heats of formation of the optimized complexes from those of the optimized isolated molecules differentiate the behavior of the anionic heads between the agonist and antagonist compounds. Affinity and stabilization are confirmed by computing ab initio STO−3G ionization potentials and interaction energies taking into account counterpoise corrections. Results show a decrease of the interaction energy from GABA and TACA (−54.9 and −49.4 kcal/mol) to isomuscimol (−35.6 kcal/mol), via muscimol (−46.0 kcal/mol). The low interaction energy of the 5‐isoxazolols as isomuscimol compared to the 3‐isoxazolols, as muscimol, may explain their antagonist character. Copyright © 1988 John Wiley & Sons, Inc.