Synthesis and pharmacological profile of conformationally rigidified glutamic acid homologues selective for the NMDA receptor

Glutamate (Glu) is the main excitatory neurotransmitter in the mammalian CNS and mediates neurotransmission across most excitatory synapses. The role played by NMDA receptors in excitotoxicity has driven the search for antagonists as neuroprotective agents. The NMDA receptors blocking approach could be applied to treat several acute and chronic pathologies. Starting from the structure of the endogenous ligand (S)-Glu, it is possible to obtain ligands selective for a specific receptor subtype by means of the conformational rigidification and the homologation of the amino acidic chain. By using a combination of these two strategies, we have previously synthesized highly selective NMDA antagonists. Taking these molecules as model compounds, in my Ph.D. work I investigated the effect on the activity/selectivity profile of a) a further increase in the length of the amino acidic chain, b) the introduction of an additional rigidification in the side chain, c) the bioisosteric replacement of the distal carboxylic acid with a phosphonic acid group, d) the replacement of the isoxazoline moiety with a pyrazoline nucleus bearing a phenyl ring appended at the N-1 position. In order to investigate the relevance of the absolute configuration for the biological activity, the compounds were then prepared as pure enantiomers. All new compounds were tested in binding and electrophysiology assays on native an cloned NMDA receptors.