Design and development of excitatory amino acid related compounds for protection against senile neuronal death

Potent agonist for metabotropic glutamate receptors，such as L-CCG-I，DCG-IV，cis-MCG-I and trans-MCG-I were found in the present study.All of them are derivatives of2-(Carboxyclopropyl)glycine(CCG)，which provided useful information about relationship between activation of glutamate receptors and conformation of agonists.Their conformation of glutamate skeleton is an extended form，and they reduced monosynaptic excitation in the isolated newborn rat spinal cord，by inhibiting transmitter release from nerve terminal.These four agonists for metabotropic glutamate receptors inhibited forskolin-stimulated cyclic AMP content in a dose dependent manner，and they demonstrated potent CNS depressant actions in the rat.Among them DCG-IV was the most potent.Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were clarified with special reference to kainate excitotoxicity.Intraventricular DCG-I·V caused selective neuron damage at relatively high doses in the cingulate cortex and the hippocampal subiculum in the rat，but other agonists did not cause neuron damage in the rat.DCG-IV considerably alleviated the kainate-induced limbic seizures。At relatively low doses，DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity，when intraventricularly injected to the rat.These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by excitatory amino acids.

Potent agonist for metabotropic glutamate receptors, such as L-CCG-I,DCG-IV,cis-MCG-I and trans-MCG-I were found in the present study. All of them are derivatives of 2- (carboxycyclopropyl) glycine (CCG), which provided useful information about relationship between activation of glutamate receptors and conformation of agonists. Their conformation of glutamate skeleton is an extended form, and they reduced monosynaptic excitation in the isolated newborn rat spinal cord, by inhibiting transmitter release from nerve terminal. These four agonists for metabotropic glutamate receptors inhibited forskolin-stimulated cyclic AMP content in a dose dependent manner, and they demonstrated potent CNS depressant actions in the rat. Among them DCG-IV was the most potent. Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were clarified with special reference to kainate excitotoxicity. Intraventricular DCG-I・V caused selective neuron damage at relatively high doses in the cingulate cortex and the hippocampal subiculum in the rat, but other agonists did not cause neuron damage in the rat.DCG-IV considerably alleviated the kainate-induced limbic seizures. At relatively low doses, DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity, when intraventricularly injected to the rat. These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by excitatory amino acids.