Synthesis, NMDA receptor antagonist activity, and anticonvulsant action of 1-aminocyclobutanecarboxylic acid derivatives

J Med Chem. 1994 Dec 9;37(25):4288-96. doi: 10.1021/jm00051a005.

Abstract

A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones was shown by compounds in which the 3-substituent was, or contained, a 2'-carboxyethyl or 2'-phosphonoethyl moiety. Substances 4b, 24, 35, and 40 were more potent than the standard NMDA receptor antagonist, D-2-amino-5-phosphonopentanoate (D-AP5) as NMDA antagonists in this preparation, and about equipotent with [3-(+/-)-2-carboxypiperazin-4-yl)-1-propyl]phosphonate (CPP). Anticonvulsant activity, as assessed following intracerebroventricular injection into audiogenic DBA/2 mice, generally paralleled NMDA receptor antagonist activity.

Publication types

  • Comparative Study

MeSH terms

  • Acoustic Stimulation
  • Amino Acids / chemistry*
  • Amino Acids / pharmacology
  • Amino Acids / therapeutic use
  • Amino Acids, Cyclic*
  • Animals
  • Animals, Newborn
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / therapeutic use
  • Binding Sites
  • Computer Simulation
  • Mice
  • Mice, Inbred DBA
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Motor Neurons / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Seizures / etiology
  • Seizures / prevention & control
  • Spinal Cord / metabolism
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Amino Acids, Cyclic
  • Anticonvulsants
  • Receptors, N-Methyl-D-Aspartate
  • 1-aminocyclobutanecarboxylic acid