ADX-47273 is a brain-penetrating, potent and selective metabotropic glutamate receptor 5 (mGlu5; mGluR5) positive allosteric modulator (PAM) that enhances glutamate-stimulated Ca2+ response in rat cortical astrocytes (EC50 = 170 nM, Emax = 380%; [glutamate] = EC20 = 200 nM) via direct mGlu5 binding in a MPEP-, but not Quisqualate-, competitive manner (Ki = 4.3 μM against 2 nM MPEP; rat mGlu5 HEK293) with little mGlu5 agonist activity, no potency toward other rat/human family III GPCRs (mGlu1–8 and GABA-B), nor affinity to 56 GPCRs/transporters/enzymes/ion channels. ADX-47273 shows in vivo antipsychotic-like and procognitive efficacy in mice and rats in vivo (1-300 mg/kg i.p.) with good pharmacokinetic properties (B/P ratio >2, bioavailability ∼40%, T1/2 ∼2 hrs in rats).
Brain-penetrant, potent and selective mGlu5 (mGluR5) positive allosteric modulator (PAM) with antipsychotic and procognitive efficacy in mice and rats in vivo.
Evidence is emerging that positive and negative modulation of the metabotropic glutamate (mGluR5) receptors has the potential for treating cognitive deficits and neuroprotection associated with psychiatric and neurodegenerative diseases, respectively. Sleep and synchronisation of disparate neuronal networks are critically involved
Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl-d-aspartate (NMDA) receptors, and activation
Learning & memory (Cold Spring Harbor, N.Y.), 20(8), 438-445 (2013-07-23)
Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal
The Journal of pharmacology and experimental therapeutics, 327(3), 827-839 (2008-08-30)
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response
Journal of biomolecular screening, 21(10), 1054-1064 (2017-02-01)
Because neurons are difficult to obtain from humans, generating functional neurons from human induced pluripotent stem cells (hiPSCs) is important for establishing physiological or disease-relevant screening systems for drug discovery. To examine the culture conditions leading to efficient differentiation of
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