Synthesis of 3-hydroxy- and 3-carboxy-Delta(2)-isoxazoline amino acids and evaluation of their interaction with GABA receptors and transporters

A series of 3-hydroxy- and 3-carboxy-Delta(2)-isoxazoline amino acids, structurally related to the GABA(A) agonist THIP and to the GABA uptake inhibitors THPO and exo-THPO, was prepared by means of synthetic strategies involving the 1,3-dipolar cycloaddition of nitrile oxides. All derivatives were submitted to a pharmacological investigation at both GABA receptors and transporters. Unfortunately, all amino acids were devoid of activity except for a very low affinity at GABAA receptors, displayed by compounds 8 and 17.