CHPG

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CHPG is a selective mGlu5 metabotropic glutamate receptor agonist.

The mGlu family of G-protein-linked glutamate receptors currently comprises eight members. 3,5-dihydroxyphenylglycine can activate specifically Group I mGlu receptors, which have been found to regulate multiple effects in the vertebrate brain.

In vitro: (R,S)-2-Chloro-5-hydroxyphenylglycine [CHPG] selectively activated mGlu5a receptors with no activation of mGlu1a receptors. This selective mGlu5 receptor agonist also enhances NMDA-induced depolarizations in rat hippocampalslices. CHPG may be used to study the role of mGlu5 receptors in the CNS [1].

In vivo: To compare the effects of treatment with the newly developed selective mGluR5 antagonist MPEP and the selective mGluR5 agonist CHPG in a rat intraluminal filament model of temporary middle cerebral artery occlusion (MCAo), rats, after induction of ischemia for 2 h, were administered MPEP or CHPG (i.c.v.) beginning 15 or 135 min. measured After either 22 or 70 h of reperfusion measured infarct size, and quantified neurological function at 2, 24, 48 and 72 h. 24 h infarct volumes after treatment with MPEP or CHPG at 15 min were reduced by 61 and 44%, respectively. The neuroprotective effects were dose-dependent. The neuroprotective effects were eliminated by delaying MPEP treatment until 135 min. In other studies, with early MPEP treatment (15 min) at optimal doses, infarct volume was reduced by 44% at 72 h, being correlated with significant neurological recovery [2].

Clinical trial: Clinical study has been conducted.

References:
[1] Doherty AJ, Palmer MJ, Henley JM, Collingridge GL, Jane DE.  (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but no mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology. 1997 Feb;36(2):265-7.
[2].  Bao WL, Williams AJ, Faden AI, Tortella FC. Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia. Brain Res. 2001 Dec 20;922(2):173-9.

The selective mGluR5 agonist CHPG attenuates SO2-induced oxidative stress and inflammation through TSG-6/NF-kappaB pathway in BV2 microglial cells.[Pubmed:25953665]

Neurochem Int. 2015 Jun-Jul;85-86:46-52.

Sulfur dioxide (SO2) is a common air pollutant and can cause harmful insults on neurons. Microglial activation has been implicated in the signaling cascades that contribute to neuronal cell death in various neurological disorders. In the present study, we found that SO2 derivatives decreased cell viability via inducing oxidative stress, inflammatory responses and apoptotic cell death in BV2 microglial cells. Pretreatment with (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, significantly attenuated the SO2-induced cytotoxicity, which was fully prevented by the mGluR5 antagonist MPEP. CHPG increased the expression of TNF-alpha stimulated gene/protein 6 (TSG-6), but decreased the activation of nuclear factor-kappaB (NF-kappaB) after SO2 derivatives treatment in BV2 cells. In addition, knockdown of TSG-6 expression by specific targeted short interfering RNA (siRNA) partially reversed the protection induced by CHPG. Therefore, our findings reveal a mechanistic basis for exploring the association between SO2 exposure and neurological disorders, and also for opening up therapeutic approaches of ameliorating neuronal injury resulting from exposure in atmospheric polluting environment.

The metabotropic glutamate mGluR5 receptor agonist CHPG stimulates food intake.[Pubmed:20505551]

Neuroreport. 2010 Jul 14;21(10):704-8.

The metabotropic glutamate receptor 5 (mGluR5) has been suggested to modulate energy balance. For example, mGluR5 antagonists inhibit food intake in rodents and mGluR5 knockout mice resist diet-induced obesity. However, nonspecific effects can reduce food intake. Thus, to further support the role of mGluR5 in feeding behaviour, we evaluated if the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) would induce the opposite effect, i.e. increased food intake in rats. Intracerebroventricularly injected CHPG (0.5-1.5 micromol) induced a dose-dependent stimulation of food intake (349% increase at 2 h with 1.5 micromol). The mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (10 mg/kg intraperitoneally) reduced 24 h food intake, without altering CHPG-induced feeding. These findings further support a physiologically relevant role of mGluR5 in appetite regulation.

No improvement of functional and histological outcome after application of the metabotropic glutamate receptor 5 agonist CHPG in a model of endothelin-1-induced focal ischemia in rats.[Pubmed:17239461]

Neurosci Res. 2007 Apr;57(4):499-503.

The role of group I metabotropic glutamate receptors (mGluRs) in neurodegeneration is as yet unclear as mGluR1/5 antagonists and agonists yielded contradictory effects in different disease models. In the present study, we examined the neuroprotective potency of the selective mGluR5 agonist, (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), in endothelin-1(ET-1)-induced focal ischemia in rats. In addition to the effect of CHPG on the histologically defined infarct size, we studied its influence on sensorimotor impairments in the ladder rung walking test at late time points up to 4 weeks after the ischemic insult. Rats were treated i.c.v. with an injection of 1mM CHPG beginning 10min after the application of ET-1. Histological analyses 4 weeks after ET-1-induced ischemia demonstrated only a small, insignificant reduction in infarct size after CHPG application. In accordance with this result, there were no significant effects of the used CHPG concentration on sensorimotor impairments in the ladder rung walking test. In conclusion, our data point to the restricted value of CHPG as a neuroprotectant after transient focal ischemia and to the importance of evaluating neuroprotective effects at late post-ischemic time points.

The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway.[Pubmed:22211238]

Int J Mol Med. 2012 Apr;29(4):630-6.

Group I metabotropic glutamate receptors (mGluRs) have been implicated in the pathophysiology of central nervous system injury, but the role of mGluR5 in traumatic brain injury (TBI) remains unclear. In the present study, we investigated the neuroprotective potency of (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), a selective mGluR5 agonist, for protecting against TBI in both in vitro and in vivo models. Primary cortical neurons were treated with 1 mM CHPG in an in vitro preparation 30 min before TBI, and 250 nM CHPG was injected into the right lateral ventricle of rats 30 min before TBI was induced in in vivo studies. The results showed that CHPG significantly attenuated lactate dehydrogenase (LDH) release and neuronal apoptosis and reduced lesion volume. Compared to the control or vehicle group, the phosphorylation levels of extracellular signal-regulated kinase (ERK) and Akt were increased in the presence of CHPG, even following the induction of TBI. Furthermore, treatment with either the ERK inhibitor PD98059 or Akt inhibitor LY294002 partially reversed the CHPG's neuroprotective effects. These data suggest that CHPG minimizes brain damage after induction of TBI both in vitro and in vivo, and that these protective effects were possibly mediated by activation of the ERK and Akt signaling pathways. Thus, potentiating mGluR5 activity with selective agonists such as CHPG may be useful for the treatment of traumatic brain injury.

Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia.[Pubmed:11743947]

Brain Res. 2001 Dec 20;922(2):173-9.

Activation of group I metabotropic glutamate receptors (mGluR) has been implicated in the pathophysiology of acute central nervous system injury. However, the relative roles of the two group I subtypes, mGluR1 or mGluR5, in such injury has not been well examined. We compared the effects of treatment with the newly developed, selective mGluR5 antagonist 2-methyl-6-phenylethynylpyridine (MPEP) and the selective mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) in a rat intraluminal filament model of temporary middle cerebral artery occlusion (MCAo). Rats were administered MPEP or CHPG i.c.v. beginning 15 or 135 min after induction of ischemia for 2 h. Infarct size was measured after either 22 or 70 h of reperfusion, and neurological function was quantified at 2, 24, 48 and 72 h. Treatment with MPEP or CHPG at 15 min reduced 24 h infarct volume by 61 and 44%, respectively. The neuroprotective effects were dose dependent. Delaying MPEP treatment until 135 min eliminated the neuroprotective effects. In other studies, using early MPEP treatment (15 min) at optimal doses, infarct volume was reduced by 44% at 72 h and this was correlated with significant neurological recovery. These data suggest that both MPEP and CHPG are neuroprotective when administered after focal cerebral ischemia. In separate, recent studies we found that although MPEP does act as an mGluR5 antagonist and blocks agonist induced phosphoinositide hydrolysis, it also serves as a non-competitive NMDA antagonist; in contrast, other results indicate that CHPG mediated neuroprotection may reflect anti-apoptotic activity. Therefore, both types of compounds may prove to have therapeutic potential for the treatment of stroke.

Antagonism of the mGlu5 agonist 2-chloro-5-hydroxyphenylglycine by the novel selective mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) in the thalamus.[Pubmed:10455248]

Br J Pharmacol. 1999 Jul;127(5):1057-9.

Our previous work has shown that Group I mGlu receptors participate in thalamic sensory processing in vivo. However, unequivocal demonstration of mGlu5 participation has not been possible due to the lack of specific ligands. We have therefore made a preliminary study of the in vivo actions of the agonist (R,S)-2-Chloro-5-hydroxyphenylglycine [CHPG] and the novel mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine [MPEP] in order to characterize their suitability for functional studies. Iontophoretically administered MPEP selectively antagonized excitatory responses of single rat thalamic neurones to CHPG compared to the broad-spectrum mGlu agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate. In contrast, the established mGlu1 and mGlu5 antagonist (S)-4-carboxyphenylglycine reduced responses to both agonists. These findings are the first demonstration of an in vivo action of CHPG and its antagonism by a selective mGlu5 antagonist. Furthermore MPEP appears to be a good tool for functional studies of mGlu5.

Potentiation of NMDA and AMPA responses by the specific mGluR5 agonist CHPG in spinal cord motoneurons.[Pubmed:10530818]

Neuropharmacology. 1999 Oct;38(10):1569-76.

The specific metabotropic glutamate receptor (mGluR)5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) is able to potentiate NMDA and AMPA responses recorded from ventral roots of the isolated hemisected baby rat spinal cord. Previously we have demonstrated that activation of group I mGluRs (mGluR1 and mGluR5) with the broad spectrum mGluR agonist 1S,3R-1-amino-1,3-cyclopentanedicarboxylate (ACPD) produced potentiation of ionotropic glutamate responses. In contrast to ACPD-induced potentiation, however, no evidence for an involvement of protein kinase C (PKC) is found in the CHPG-induced potentiation of both NMDA and AMPA depolarization because the PKC blockers chelerythrine chloride or calphostin C did not antagonize this effect. Moreover, in the absence of Ca2+ in the perfusing medium or depleting intracellular Ca2+ stores with thapsigargin or dantrolene did not modify the CHPG-induced enhancement of NMDA depolarizations. Phorbol-12,13-diacetate (PDA), on the other hand, was able to attenuate this effect, which was reversed by chelerythrine chloride. These results suggest that both mGluR5 and mGluR1 may act to enhance ionotropic glutamate responses but the two types of mGluRs may have different intracellular mechanisms of action.

(RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but no mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus.[Pubmed:9144665]

Neuropharmacology. 1997 Feb;36(2):265-7.

A new phenylglycine derivative, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), has been synthesized and shown to selectively activate mGlu5a receptors, compared to mGlu1 alpha receptors, when expressed in CHO cells. This selective mGlu5 receptor agonist also potentiates NMDA-induced depolarizations in rat hippocampal slices. CHPG may be a useful tool for studying the role of mGlu5 receptors in the central nervous system.

CHPG is a selective mGluR5 agonist, and attenuates SO2-induced oxidative stress and inflammation through TSG-6/NF-κB pathway in BV2 microglial cells. CHPG protects against traumatic brain injury (TBI) in vitro and in vivo by activation of the ERK and Akt signaling pathways.

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