Synthesis of l‐Tricholomic Acid Analogues and Pharmacological Characterization at Ionotropic Glutamate Receptors

The synthesis of analogues of the natural compound l‐tricholomic acid and of its threo diastereoisomer was accomplished in order to explore their affinity for glutamate ionotropic receptors. In this study, fourteen new unnatural amino acids, characterized by a 3‐hydroxy‐▵2‐isoxazoline or 3‐hydroxy‐▵2‐pyrazoline‐skeleton, were obtained exploiting, as key reaction, a 1,3‐dipolar cycloaddition or an intramolecular cyclization. Fourteen analogues of the natural compound l‐tricholomic acid and of its threo diastereoisomer have been designed and synthesized to explore their affinity for glutamate ionotropic receptors. The new derivatives, characterized by a 3‐hydroxy‐▵2‐isoxazoline or 3‐hydroxy‐▵2‐pyrazoline‐skeleton, were obtained exploiting, as key reaction, a 1,3‐dipolar cycloaddition or an intramolecular cyclization reaction. Binding affinities of the synthesized amino acids were determined at native AMPA, KA, and NMDA receptors and the results could help to design new selective glutamate receptor ligands.