ATPA and thio-ATPA are semirigid analogs of the excitatory neurotransmitter (S)-glutamic acid. (S)-ATPA and (S)-thio-ATPA are potent and selective GluR5 receptor agonists. X-ray structure determination of the zwitterions of (RS)-ATPA and (R)-thio-ATPA has been performed. Furthermore, quantum chemical ab initio calculations have been carried out on the tautomeric heterocyclic substructures 4,5-dimethyl-3-isoxazolol and 4,5-dimethyl-3- isothiazolol. Very high level ab initio calculations (including triple-ζ basis set and treatment of electron correlation) are necessary for a consistent theoretical description of the heterocyclic rings of these compounds. Results for the aqueous phase properties (PB-SCRF method, combined with density functional theory) are chemically reasonable and in agreement with experimental data. While the 3-isoxazolol tautomer of the zwitterionic amino acid ATPA predominates in all phases, the 3(2H)-isothiazolone tautomer of the zwitterionic amino acid thio-ATPA predominates in the crystal structure (3:1) and most likely in weakly acidic aqueous solution.