N-, alpha-, and beta-Substituted 3-Aminopropionic acids: design, syntheses and antiseizure activities.
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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Department of Chemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Wainman
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Weaver
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D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D004597:Electroshock / Q000379:methods; D005998:Glycine / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D010433:Pentylenetetrazole / Q000494:pharmacology / Q000633:toxicity; D010862:Pilocarpine / Q000494:pharmacology / Q000633:toxicity; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D018675:Toxicity Tests; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; D005680:gamma-Aminobutyric Acid; D005998:Glycine; D010433:Pentylenetetrazole