N-, α-, and β-Substituted 3-Aminopropionic acids: design, syntheses and antiseizure activities Original Research Article

A treatment for epilepsy is proposed based on analogues of 3-aminopropionic acid (β-alanine), a putative neurotransmitter in the central nervous system (CNS). A model three point pharmacophore was proposed based on modelling data obtained from the study of antagonists for both the glial γ-aminobutyric acid (GABA)-uptake site and the glycine co-agonist site of N-methyl-d-aspartate (NMDA) receptor. Three series of 3-aminopropionic acids containing, N-, α-, and β-substituents, were designed and synthesized to probe the position and the size of a lipophilic binding pocket within the proposed pharmacophore. These analogues were tested in vivo for both their antiseizure activities and their neurologic toxicities. Among the fourteen novel 3-aminopropionic acids synthesized, eight were found to have promising antiseizure activity. This study shows that substitution on the N-terminus confers the greatest antiseizure activity, particularly against pilocarpine-induced seizures.