Synthesis of (3-hydroxy-pyrazolin-5-yl)glycine based ligands interacting with ionotropic glutamate receptors

• Selective ligands for ionotropic Glu receptors are important pharmacological tools.
• l-Tricholomic acid is a naturally occurring nonselective AMPA/KA receptor ligand.
• Increasing the molecular complexity may enhance the receptor selectivity.
• New AMPA and KA ligands have been designed based on the 3-hydroxy-pyrazolin-5-yl glycine scaffold.

Following the concept that increasing the molecular complexity may enhance the receptor selectivity, we replaced the 3-hydroxy-isoxazoline ring of model compound tricholomic acid with a 3-hydroxy-pyrazoline ring, which could be variously decorated at the N1 position, inserting groups characterized by different electronic and steric properties. Binding assays on rat brain synaptic membranes showed that, depending on the nature of the substituent, some of the new synthesized ligands interacted with either AMPA or KA receptors, with affinities in the mid-micromolar range.

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