MTEP hydrochloride

IC50: 5 nM

MTEP is a selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist.

The mGluRs are classified into three groups: group I (mGluR1 and 5), group II (mGluR2 and 3) and group III (mGluR4, 6, 7 and 8). mGluR5 belonging to group I is excitatory, mainly localized at the edge of axo-spinous and axodendritic synaptic junctions.

In vitro: Like MPEP, MTEP showed a nanomolar affinity for mGluR5, but seemed to be superior to MPEP in term of specificity. MTEP did not influence mGluR2, mGluR7, NMDA, AMPA or kainate receptors, while inhibited MAOA at a concentration three times higher than MPEP. Moreover, recent study indicated that MTEP was five times stronger that MPEP as an anxiolytic compound [1].

In vivo: MTEP with doses between 0.5 and 3 mg/kg was found to decrease the haloperidol-induced muscle rigidity, which was measured as an increased muscle resistance of the rat hind leg. The longest and strongest effect was observed with the dose of 1 mg/kg. MTEP was also found to reduce the haloperidol-induced increase in electromyographic activity recorded in the tibialis anterior and gastrocnemius muscles. 3 and 5 mg/kg of MTEP could inhibit the haloperidol- induced catalepsy [1].

Clinical trial: N/A

Reference:
[1] Ossowska K,Konieczny J,Wolfarth S,Pilc A.  MTEP, a new selective antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), produces antiparkinsonian-like effects in rats. Neuropharmacology.2005 Sep;49(4):447-55.

Environmental condition alters amphetamine self-administration: role of the MGluR(5) receptor and schedule of reinforcement.[Pubmed:26211759]

Psychopharmacology (Berl). 2015 Oct;232(20):3741-52.

RATIONALE: Evidence suggests that differential rearing influences the function of a receptor subtype critical for maintaining glutamate homeostasis. Maintaining homeostatic glutamatergic function may be an important protector against drug abuse. OBJECTIVE: This study sought to determine if differential rearing influences the function of a receptor critical for glutamate homeostasis, which could in turn affect rates of amphetamine self-administration. METHODS: Rats were assigned to enriched (EC), isolated (IC), or standard (SC) conditions. After rearing for 30 days, rats were trained to lever press for sucrose reinforcement before the implantation of indwelling jugular catheters. After reaching stable responding for amphetamine (0.03 or 0.1 mg/kg/infusion), rats were injected with five doses (0, 0.3, 1.0, 3.0, and 5.0 mg/kg) of the mGluR5 antagonist, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl) pyridine hydrochloride (MTEP), 30 min before self-administration sessions. Following fixed-ratio (FR-1) testing, rats were administered identical doses of MTEP on a progressive-ratio (PR) reinforcement schedule. RESULTS: MTEP (3.0 mg/kg) attenuated FR-1 self-administration (0.03 mg/kg/infusion) in IC rats. MTEP also dose-dependently attenuated amphetamine self-administration (0.1 mg/kg/infusion) during FR-1 and PR sessions, with 5.0 mg/kg MTEP attenuating amphetamine self-administration in IC and SC rats and 3.0 mg/kg MTEP attenuating amphetamine self-administration in EC and SC rats. PR results also revealed that IC rats not treated with MTEP were more motivated to self-administer the higher dose of amphetamine. CONCLUSIONS: These results suggest that the mGlu5 receptor mediates differences in drug-taking behavior among differentially reared rats. Isolation also decreased sensitivity to MTEP, suggesting that environmental factors alter glutamate homeostasis which subsequently affects sensitivity and motivation to self-administer amphetamine.

Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 positive allosteric modulator.[Pubmed:25031220]

J Psychopharmacol. 2014 Oct;28(10):935-46.

Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fear-conditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5-mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multi-electrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit.

Activation of type 5 metabotropic glutamate receptor promotes the proliferation of rat retinal progenitor cell via activation of the PI-3-K and MAPK signaling pathways.[Pubmed:26902516]

Neuroscience. 2016 May 13;322:138-51.

The metabotropic glutamate receptor 5 (mGluR5) regulates neurogenesis in the brain, but the effect of mGluR5 on retinal progenitor cells (RPCs) remains unknown. In this study, we found that mGluR5 promoted the proliferation of rat RPCs with activation of the phosphatidylinositol-3-kinase (PI-3-K) and mitogen-activated protein kinase (MAPK) signaling pathways in vitro. The mGluR5 agonist (S)-3,5-dihydroxyphenylglycine hydrate (DHPG) increased the cellular viability in a concentration- and time-dependent manner, whereas the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine hydrochloride (MTEP) had the opposite effect, as shown by 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTT) assay. Treatment with DHPG (100 muM) also promoted the proliferation of RPCs, as indicated by 5-Bromo-2-deoxyUridine (BrdU) staining and flow cytometry, and likewise, MTEP (100 muM) and mGluR5 knockdown abolished the action of mGluR5 activity. Western blot demonstrated that the activation of mGluR5 enhanced the expression of Cyclin D1 and the phosphorylation level of PKC however, MTEP or mGluR5 knockdown also abrogated the effect of DHPG on RPCs. Furthermore, we found that activation of the extracellular signal-regulated protein kinase (ERK) and protein kinase B (AKT) signaling pathways was involved in the proliferation of RPC. After DHPG treatment, the levels of both p-ERK1/2 and p-AKT increased in a time-dependent manner. Then we used MTEP, mGluR5 knockdown, the ERK1/2 inhibitor U0126 and the AKT inhibitor LY294002 to pretreat the cells, and all of them clearly eliminated the influence of DHPG. These results demonstrated that mGluR5 regulates neurogenesis in RPCs through the MAPK and PI-3-K signaling pathways, and these findings may motivate a pharmacological study investigating a potential mechanism for the treatment of retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD).

Activation of lateral hypothalamic mGlu1 and mGlu5 receptors elicits feeding in rats.[Pubmed:24219858]

Neuropharmacology. 2014 Apr;79:59-65.

Metabotropic glutamate receptors (mGluRs) have been popular drug targets for a variety of central nervous system (CNS) disease models, ranging from seizures to schizophrenia. The current study aimed to determine whether mGluRs participate in lateral hypothalamic (LH) stimulation of feeding. To this end, we used satiated adult male Sprague-Dawley rats stereotaxically implanted with indwelling bilateral LH guide cannulas to determine if injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a broad mGluR group I and II agonist, would elicit feeding. Administration of 100 nmol ACPD induced feeding with a short latency. Similarly, unilateral LH injection of the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) elicited significant feeding beginning 60 min postinjection and continuing until 4 h postinjection. Administration of the mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) produced a smaller delayed feeding response. These delayed but prolonged eating responses suggest that activation of LH mGluR1 and/or mGluR5 might be sufficient to elicit feeding. To determine which subtypes were involved, LH DHPG injections were preceded by LH injection of either the group I antagonist n-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), the mGluR1 antagonist 6-amino-n-cyclohexyl-n,3-dimethylthiazolo[3,2-a]benzimi dazole-2-carboxamide hydrochloride (YM-298198) or the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), and food intake was measured. PHCCC blocked DHPG-elicited feeding, and each of the other antagonists produced significant feeding suppression. These findings suggest roles for mGluR1 and/or mGluR5 in lateral hypothalamic circuits capable of stimulating feeding behavior.

The influence of ionotropic and metabotropic glutamate receptor ligands on anxiety-like effect of amphetamine withdrawal in rats.[Pubmed:23623810]

Prog Neuropsychopharmacol Biol Psychiatry. 2013 Aug 1;45:242-9.

Chronic amphetamine use results in anxiety-like states after drug cessation. The aim of the study was to determine a role of ionotropic and metabotropic glutamate receptor ligands in amphetamine-evoked withdrawal anxiety in the elevated plus-maze test in rats. In our study memantine (8 and 12 mg/kg), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist did not reduce amphetamine withdrawal anxiety. Acamprosate (NMDA and metabotropic glutamate 5 receptor (mGluR5) antagonist) at the dose 200 and 400mg/kg showed anxiolytic-like effect, thus increasing the percent of time spent in open arms and a number of open arm entries. mGluR5 selective antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine hydrochloride) and mGluR2/3 agonist, LY354740 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), caused effects similar to acamprosate at doses 1.25-5mg/kg and 2.5-5mg/kg, respectively. None of the glutamate ligands influenced locomotor activity of rats when given to the saline-treated group. Taking into account the positive correlation between amphetamine withdrawal-induced anxiety and relapse to amphetamine taking, our results suggest that modulation of mGluRs may prevent relapse to amphetamine and might pose a new direction in amphetamine abuse therapy.

Metabotropic glutamate receptor mGlu5 is a mediator of appetite and energy balance in rats and mice.[Pubmed:15590770]

J Pharmacol Exp Ther. 2005 Apr;313(1):395-402.

The metabotropic glutamate receptor subtype mGlu5 modulates central reward pathways. Many transmitter systems within reward pathways affect feeding. We examined the potential role of mGlu5 in body weight regulation using genetic and pharmacological approaches. Adult mice lacking mGlu5, mGluR5-/-, weighed significantly less than littermate controls (mGluR5+/+, despite no difference in ad libitum food intake. After overnight food deprivation, mGluR5-/- mice ate significantly less than their mGluR5+/+ controls when refeeding. When on a high fat diet, mGluR5-/- mice weighed less and had decreased plasma insulin and leptin concentrations. The selective mGlu5 antagonist MTEP [3-[(2-methyl-1,3-thiazol-4-yl)-ethynyl]-pyridine; 15 mg/kg s.c.] reduced refeeding after overnight food deprivation in mGluR5+/+, but not mGluR5-/- mice, demonstrating that feeding suppression is mediated via a mGlu5 mechanism. MTEP (1-10 mg/kg) decreased night-time food intake in rats in a dose-related manner. At 10 mg/kg, MTEP injected at 8.5, 4.5, or 0.5 h before refeeding reduced overnight food intake by approximately approximately 30%. Diet-induced obese (DIO) and age-matched lean rats were treated for 12 days with MTEP (3 or 10 mg/kg/day s.c.), dexfenfluramine (3 mg/kg/day s.c.), or vehicle. Daily and cumulative food intakes were reduced in DIO rats by MTEP and dexfenfluramine. Weight gain was prevented with MTEP (3 mg/kg), and weight and adiposity loss was seen with MTEP (10 mg/kg) and dexfenfluramine. Caloric efficiency was decreased, suggesting increased energy expenditure. In lean rats, similar, although smaller, effects were observed. In conclusion, using genetic and pharmacological approaches, we have shown that mGlu5 modulates food intake and energy balance in rodents.

Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling.[Pubmed:15275823]

Neuropharmacology. 2004 Sep;47(3):342-50.

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic drugs including the involvement of group I metabotropic glutamate (mGlu) receptors. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), i.e. the most potent mGlu5 antagonist, was evaluated in established models of anxiety after single or repeated administration. We also studied if the anxiolytic effect of MTEP is mediated by mechanism involving the GABA-benzodiazepine (BZD) receptor complex. Experiments were performed on male Wistar rats or male Albino Swiss mice. The anxiolytic-like effects of MTEP were tested in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MTEP (0.3-3.0 mg/kg) induced anxiolytic-like effects in the conflict drinking test (after single and repeated administration) and in the elevated plus-maze test in rats. In the four-plate test in mice, it exerted anxiolytic activity at a dose of 20 mg/kg. MTEP had no effect on the locomotor activity of animals. The anxiolytic-like effect of MTEP was not changed by BZD antagonist flumazenil. Moreover, a synergistic interaction between non-effective doses of MTEP and diazepam was observed in the conflict drinking test. These data suggest that selective mGlu5 receptor antagonists mediated anxiolysis is not dependent on GABA-ergic system and that these agents may play a role in the therapy of anxiety.

5-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine: a highly potent, orally active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist with anxiolytic activity.[Pubmed:15225713]

Bioorg Med Chem Lett. 2004 Aug 2;14(15):3993-6.

Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.

3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity.[Pubmed:12519057]

J Med Chem. 2003 Jan 16;46(2):204-6.

2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.

Reduced stress-induced hyperthermia in mGluR5 knockout mice.[Pubmed:12473093]

Eur J Neurosci. 2002 Dec;16(11):2241-4.

It hs been suggested that metabotropic glutamate receptor subtype 5 (mGluR5) play a role in the expression of anxiety, based on anxiolytic-like effects of the selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) in rodent models of anxiety, including stress-induced hyperthermia (SIH). To examine the suggested role of mGlu5 receptors in the expression of anxiety, we examined the stress response in mice lacking mGluR5 in several variations of the SIH procedure. In this paradigm, stress causes a mild increase in body temperature that can be blocked by known anxiolytic agents. Three procedures were employed: classical SIH using rectal-probe measurement of body temperature, and radiotelemetric measurement of body temperature in response to either saline injection or to the introduction of an intruder into the home cage. In all three procedures the mGluR5-knockout mice displayed a significant attenuation of the hyperthermic response to stress compared to littermate wild-type control mice. To confirm that our observations were likely to be due to the absence of mGluR5 in the knockout mice we also tested the effect of the recently described selective mGluR5 antagonist MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) in both the wild-type and mGluR5 knockout mice. Administration of MTEP in the wild-type mice, but not the mGluR5 knockout mice, attenuated SIH. That the mGluR5 knockout mice displayed an anxiolytic-like phenotype and that the mGluR5 antagonist, MTEP, showed a anxiolytic-like effect only in mice possessing mGluR5 further supports the suggestion that mGluR5 antagonists may be useful in the treatment of anxiety.

MTEP hydrochloride is a potent, selective and non-competitive mGlu5 antagonist with an IC50 of 5 nM and a Ki of 16 nM. MTEP hydrochloride produces antiparkinsonian-like effects.

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