Synthesis, receptor binding and activity of iso and azakainoids

Bioorg Med Chem Lett. 2013 Apr 1;23(7):1949-52. doi: 10.1016/j.bmcl.2013.02.046. Epub 2013 Feb 16.


Two syntheses for the production of an unsubstituted azakainoid are described. The 1,3-dipolar cycloaddition of diazomethane with trans-dibenzyl glutaconate yields a 1-pyrazoline, which may be reduced directly to the pyrazolidine. An unexpected trans-cis isomerization is observed during Hg/Al reduction of the 1-pyrazoline NN bond. Alternatively, when TMS diazomethane is used as the dipole, the resulting 2-pyrazoline obtained after desilylation may be reduced with NaCNBH3 to provide the trans azakainate analog exclusively. The synthesis of an unsubstituted isokainoid via Michael addition is also described. Glutamate receptor binding assays revealed that the azakaniod has a moderate affinity for unspecified glutamate receptors. Membrane depolarization of Aplysia neurons upon application of the azakainoid demonstrates that it is an ionotropic glutamate receptor agonist.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aplysia
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Kainic Acid / analogs & derivatives
  • Kainic Acid / chemistry
  • Kainic Acid / pharmacology*
  • Molecular Structure
  • Neurons / cytology
  • Neurons / drug effects*
  • Receptors, Glutamate / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Aza Compounds
  • Receptors, Glutamate
  • Kainic Acid