Ligands for Metabotropic Glutamate Receptors and Inhibitors of NAALADase
Categories: “Neurodegenerative Therapeutics“
Reference #: 2004-028
N-Acetylaspartylglutamate (NAAG) is an abundant and widely distributed peptide neurotransmitter in the mammalian nervous system. NAAG activates the metabotropic glutamate mGlu(3)receptor at presynaptic sites, inhibiting the release of neurotransmitters, including glutamate. An elevated level of glutamate is associated with a number of neurological diseases and conditions, including schizophrenia, head injury, stroke, Amyotrophic Lateral Sclerosis (ALS) and prolonged epileptic seizures. Following its synaptic release, NAAG is inactivated by NAAG peptidase, also referred to as NAALAdase, leading to elevated levels of glutamate.
Georgetown researchers have discovered novel inhibitors of NAALAdase, which lead to increased NAAG levels and decreased glutamate levels. One inhibitor in particular, ZJ43, has demonstrated promising results in reducing schizophrenia-like behaviors in animal models, and thus represents a promising therapeutic lead for treating NAALAdase associated disorders and diseases.
- NAALdase inhibitor for the treatment of neurological diseases and conditions, including schizophrenia, head injury, stroke, Amyotrophic Lateral Sclerosis (ALS) and prolonged epileptic seizures
- These compounds, particularly ZJ43, exhibit potent inhibitory activity against NAALDase
Stage of Development
Preliminary animal studies conducted.
The neurotransmitter N- acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia.” Trends Pharmacol. Sci. 2005, 26(9), 477-484.
NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J. Neurochem. 2004, 89(4), 876.
Alan P. Kozikowski, Jarda T. Wroblewski and Fajun Nan
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