Prot #IS00014223: Effect of GABA Receptor Positive Allosteric Modulators on the Behavior and Memory Function in an Animal Model of Alzheimer's Disease

Project: Research project

Project Details

Description

GABAA receptors (GABAARs) mediate fast inhibitory neurotransmissions in the CNS. The GABAARs comprising α4/6, βx and γ2 subunits are located at synaptic sites, responsible for mediating phasic inhibition. The GABAARs comprising α4/6, βx subunits combined with δ subunit are enriched at extrasynaptic sites, responsible for mediating tonic inhibition (Mody, L., Neurochem. Res. 2001, 26, 907-913). The different subunit combination and localization determine the biophysical and pharmacological functions of the assembled GABAARs. The human GWAS studies have demonstrated that genetic mutations in GABAARs play a role in multiple neurological and neuropsychiatric disorders, including schizophrenia, bipolar and epilepsies (Cherlyn, SY. Et al., Neurosci Biobehav Rev. 2010, 34, 958-977; Macdonald, RL. et al. J Physiol. 2010, 34, 958-977; Macdonald, RL. et al., J Physiol. 2010, 588, 1861-1869). The role of GABAARs in depression has generated significant interest because several compounds that modulate GABAergic transmission exhibit antidepressant/mood-stabilizing effects (Kalueff, AV. Et al., Depress Anxiety 2007, 24, 495-517). Deficits in GABAergic inhibition have been proposed to play a critical role in the pathophysiology of depression (Luscher, B. et al., Mol Psychiatry 2011, 16, 383-406; Maguire, J. et al., Neuron 2008, 59, 207-213). However, increased GABA level in brain is accompanied by numerous detrimental side effects. Targeting on synaptic and extrasynaptic GABAA receptor subtypes may eliminate the need to modulate GABA levels and reduce side effects.

Neurosteroids (NAS) are biosynthesized in the brain from cholesterol or through the conversion from peripheral steroids that have potent and selective effects on the GABAA receptors (Beshir, K. et al., Front. In Neurol. 2017, 8, Article 442). The ovarian hormone progesterone and its metabolites such as allopregnanolone have shown profound effects on brain excitability (Lambert, J. et al., Trends Pharmacol. Sci. 1987, 8, 224-227). It could function as positive allosteric modulator of the GABAA receptor. There is a considerable body of evidence supporting the potential for GABAA modulation in treating a number of neurodegenerative diseases and mood disorders. However, the oral bioavailability of NASs is very low, which restricts the usage of NASs as therapeutic agents. In this project, we have synthesized a new series of NASs with enhanced drug-like properties while maintaining or improving the pharmacodynamic functions. We have established a Cl- FLIPR assay to characterize the compounds as positive allosteric modulators of GABAA receptors in vitro. In mouse brain pharmacokinetic experiments, a lead compound showed a quick Brian Blood Barrier penetration after oral dosing. We are planning to pursue this compound as a new drug candidate for CNS disorders.

To reach our goal, we would like to establish a collaboration with Dr. Hongxin Dong, MD PhD, in the department of Psychiatry and Behavioral Sciences at Northwestern University to evaluate the efficacy of this new series of compounds in animal models through a pilot study. We plan to test the compounds in the mouse models that mimic the different aspects of the behavioral and psychological symptoms and etiologies of various CNS diseases. These models use environmental stress in transgenic Alzheimer’s disease mice or drug-induced depressive mice. A battery of behavioral tests will be employed to evaluate the therapeutic effects on depression, anxiety, social behaviors and working memory. After the pilot studies we will decide the next
StatusFinished
Effective start/end date1/1/2012/31/20

Funding

  • Sparx Therapeutics, Inc. (Prot #IS00014223)

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