Development of Potent and Selective Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 2 for the Potential Treatment of Alzheimer’s Disease

Abstract

AbstractBackgroundThe metabotropic glutamate receptor 2 (mGluR2) is a group II mGluR that binds glutamate and utilizes Gi/o signaling within the central nervous system (CNS) to modulate synaptic transmission and neuronal excitation.1 The alteration of basal glutamate signaling has been implicated in a variety of neurodegenerative diseases including Alzheimer’s disease (AD).2 mGluR2 has been found to be overexpressed in the hippocampal neurons of AD patients and receptor overactivation has been shown to induce plaque formation in in vitro AD models.3, 4 Thus, the utilization of a mGluR2 negative allosteric modulator (NAM) may prevent neurodegeneration. The utility of mGluR2 NAMs for neurodegenerative diseases remains unclear due to the lack of mGluR selectivity of historical compounds.1. Niswender, C.M. and P.J. Conn, Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annual review of pharmacology and toxicology, 2010. 50: p. 295‐322.2. Li, S.H., K.S. Abd‐Elrahman, and S.S.G. Ferguson, Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases. Pharmacology & Therapeutics, 2022. 239: p. 108275.3. Lee, H.‐g., et al., Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease. Acta Neuropathologica, 2004. 107(4): p. 365‐371.4. Caraci, F., et al., Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer’s disease: selective activation of mGlu2 receptors amplifies beta‐amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Mol Pharmacol, 2011. 79(3): p. 618‐26.MethodNovel mGluR2 NAMs were synthesized using an iterative library synthetic approach to improve potency, selectivity, and provide an overall sufficient drug metabolism/pharmacokinetics (DMPK) profile. Compound potency (IC50) and selectivity were evaluated in an in vitro GIRK cell‐based T1 flux assay expressing mGluR2 or mGluR3 receptors. Lead compounds were tested in in vitro plasma protein binding assays and rat in vitro and in vivo clearance values were obtained.ResultThe successful discovery and development of a potent and selective mGluR2 NAM as an in vivo tool compound to elucidate the biological effects associated with mGluR2 antagonism was achieved.ConclusionmGluR2 NAMs may be useful therapeutic agents for the potential treatment of AD and other neurodegenerative diseases.