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Preparation and In Vivo Use of an Activity-based Probe for N-acylethanolamine Acid Amidase
Published on: November 23, 2016
N-, alpha-, and beta-Substituted 3-Aminopropionic acids: design, syntheses and antiseizure activities
C Y K Tan1, D Wainman, D F Weaver
1Department of Chemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Abstract:
A treatment for epilepsy is proposed based on analogues of 3-aminopropionic acid (beta-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 gamma-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-, alpha-, and beta-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.
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