Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity

Schlumberger, Chantal; Pietraszek, M.; Gravius, Andreas; Klein, Kai-Uwe; Greco, Sergio; Morè, Lorenzo; Danysz, Wojciech

doi:10.1016/j.ejphar.2009.09.006

Cited by 44 publications

(27 citation statements)

References 63 publications

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“…Our findings with DPFE and VU0364289 confirm and extend previous studies with earlier generation mGlu 5 PAMs, including CDPPB, ADX47273, and CPPZ (Kinney et al, 2005;Liu et al, 2008b;Schlumberger et al, 2009;Rosenbrock et al, 2010;Spear et al, 2011). In contrast, more recent studies using the mGlu 5 PAMs LSN2463359 and LSN2814617 reported only marginal antipsychotic-like effects .…”

Section: Discussionsupporting

confidence: 77%

“…9B). These data provide a point of deviation from the preclinical profile reported for another mGlu 5 PAM, ADX47273 (Schlumberger et al, 2009). It is important to note that the oral route of administration may have reduced in vivo exposure to DPFE contributing to its lack of efficacy in this model.…”

Section: Procognitive and Antipsychotic Efficacy Of Mglu 5 Modulatorsmentioning

confidence: 69%

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N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Gregory

Herman

Ramsey

et al. 2013

J Pharmacol Exp Ther

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Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu 5 ) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu 5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca 21 mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu 5 allosteric binding site and high selectivity for mGlu 5 . VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu 5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu 5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia.

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Section: Discussionsupporting

confidence: 77%

Section: Procognitive and Antipsychotic Efficacy Of Mglu 5 Modulatorsmentioning

confidence: 69%

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Gregory

Herman

Ramsey

et al. 2013

J Pharmacol Exp Ther

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“…To correlate the in vitro functional selectivity profiles with potential in vivo therapeutic effects, we evaluated the inhibition of psychostimulant or psychotomimetic-induced hyperlocomotion in mice by UNC9975, both of which are well-established pharmacological mouse models for assessing potential antipsychotic activity (27,28). We first evaluated the ability of UNC9975 to inhibit D-amphetamine-induced hyperlocomotion as detailed previously (27) in inbred C57BL/6 mice. As shown in Fig.…”

Section: Unc9975 and Unc9994 Exhibit Antipsychotic Activity In Vivo Tmentioning

confidence: 99%

Discovery of β-Arrestin–Biased Dopamine D ₂ Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

Allen

Yost

Setola

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

315

432

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Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D 2 receptor (D 2 R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D 2 R agonists that display signaling bias via β-arrestinergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin-biased D 2 R ligands. These compounds also represent unprecedented β-arrestin-biased ligands for a G i -coupled G proteincoupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G i -regulated cAMP production and partial agonists for D 2 R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin-biased D 2 R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin-biased D 2 R ligands represent valuable chemical probes for further investigations of D 2 R signaling in health and disease.functional selectivity | ligand bias G protein-coupled receptors (GPCRs) signal not only via canonical pathways involving heterotrimeric large G proteins, but also via noncanonical G protein-independent interactions with other signaling proteins including, most prominently, β-arrestins (1-4). The process by which GPCR ligands differentially modulate canonical and noncanonical signal transduction pathways is a phenomenon known as "functional selectivity" (5, 6). Such functionally selective ligands preferentially engage either canonical or noncanonical GPCR pathways (7,8). Clearly, the discovery of ligands with discrete functional selectivity profiles will be extremely useful for elucidating the key signal transduction pathways essential for both the therapeutic actions and the side effects of drugs (6). Understanding which signaling pathways contribute to antipsychotic efficacy and side effects, for instance, will in turn enable the design of better antipsychotic drug candidates and, ultimately, lead to safer and more effective therapies for patients. However, only a small number of functionally selective GPCR ligands have been reported to date (5-9). In addition to the paucity of such ligands,...

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“…Recently mGluR5 PAMs emerged as a new group of drugs that may potentiate NMDAR-mediated currents by utilizing the functional coupling between mGluR5 and NMDARs [6]. Behavioral studies demonstrated that ADX47273, which is an mGluR5 PAM, enhances NMDA-dependent functions in vitro and in vivo in adult rodents and exerts antipsychotic-like and pro-cognitive effects [7,17,29,32,33]. To our knowledge, neither fe nobam nor ADX47273 has been tested in studies of neuroprotection in brain ischemia, particularly in a rat model of perinatal asphyxia.…”

Section: Introductionmentioning

confidence: 99%

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

Makarewicz

Słomka²,

Danysz³

et al. 2015

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A b s t r a c t In the present study, we examined the effects of negative and positive allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), fenobam and ADX47273, respectively, on brain damage induced by hypoxia-ischemia (H-I) in 7-day-old rats. The test drugs were administered intraperitoneally 10 min after H-I. Rectal body temperature was measured for 2.5 h after the insult. The number of apoptotic neurons in the immature rat brain was evaluated after 24 h. The wet weight of both hemispheres was determined 14 days after H-I, and its loss was used as an indicator of brain damage. In the vehicle-treated groups, H-I reduced the weight of the ipsilateral (ischemic

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Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity

Cited by 44 publications

References 63 publications

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Discovery of β-Arrestin–Biased Dopamine D ₂ Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

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Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity

Cited by 44 publications

References 63 publications

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Discovery of β-Arrestin–Biased Dopamine D 2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

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Discovery of β-Arrestin–Biased Dopamine D ₂ Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy