Metabotropic Glutamate Receptor Subtype 5 (mGluR5) (non-competitive antagonist; IC50 = 5 nM in a Ca²⁺ flux assay; Ki = 16 nM) [1]

Compared to MPEP, MTEP is less off-target and has a different selectivity for mGluR5 than mGluR1, while MPEP has no effect on other mGluR subtypes [1].

---

MTEP is a non-competitive antagonist of mGluR5 that inhibits the phospholipase C (PLC)/Gq/IP3/DAG second messenger cascade. [1]
In an in vitro Ca²⁺ flux assay, MTEP exhibited an IC50 of 5 nM and a Ki of 16 nM for mGluR5. [1]
MTEP is highly selective for mGluR5 over other mGluR subtypes. It has minimal effect on mGluR1d (IC50 > 10 μM). [1]
Compared to MPEP, MTEP has fewer off-target effects. It shows minimal inhibition of NMDA/glycine-evoked increases in intracellular calcium at recombinant human NR1A/2B receptors (19% inhibition at 300 μM), whereas MPEP has an IC50 of 18 μM for this effect. It also inhibits monoamine oxidase A (MAO-A) with an IC50 of 30 μM. [1]
In cultured cortical neurons from rats and wild-type or mGluR5(-/-) mice exposed to NMDA- or glutamate-induced toxicity, pretreatment with MTEP (2 to 100 μM) had no neuroprotective effect. Only at a very high concentration (200 μM) did it decrease NMDA-induced cell death, suggesting that neuroprotection at high concentrations occurs through mechanisms not associated with mGluR5 modulation. [1]

The catalepsy coefficient caused by haloperidol (0.5 mg/kg, i.p.) is inhibited by MTEP (0-5 mg/kg, i.p., once) [2]. MTEP (0.3-3 mg/kg, i.p., once) is in control.

---

In vivo receptor occupancy studies with MTEP (3 mg/kg, i.p.) demonstrate significant species variability. In rat brain, it maintains >75% receptor occupancy for up to 2 hours. In mouse brain, >75% occupancy lasts for only 30-15 minutes. [1]
In a naloxone-precipitated morphine withdrawal model, MTEP (1-10 mg/kg, i.p.) dose-dependently inhibited naloxone-induced symptoms of morphine withdrawal without affecting locomotor activity. [1]
MTEP (3-30 mg/kg, i.p.) dose-dependently reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia in rodents. At 100 mg/kg, i.p., it showed CNS side effects as measured by rotarod performance and exploratory locomotor activity. [1]
Systemic administration of MTEP reduced hyperalgesia in the mouse formalin pain model and mechanical allodynia following spinal nerve ligation (SNL) in rats. It also showed anxiolytic effects in anxiety models such as the Vogel conflict and conditioned lick suppression tests. [1]

To assess the neuroprotective effects, cultured cortical neurons from rats and mice (wild-type and mGluR5-/-) were exposed to NMDA or glutamate to induce excitotoxicity. Cells were pretreated with various concentrations of MTEP (2-200 μM) before the insult. Cell death was quantified by lactate dehydrogenase (LDH) release and calcein AM assays. Pretreatment with MTEP at concentrations up to 100 μM showed no significant neuroprotection. Only at 200 μM did it reduce cell death, an effect also observed in neurons from mGluR5-/- mice, indicating an off-target mechanism. [1]

Animal/Disease Models: Male Wistar rats (215-315 g, 5-9/group) [2] Doses: 1, 3, and 5 mg/kg given Medication method: IP, inducing antidepressant-like effects in C57BL/6J mice [3]. One injection, 60 minutes after haloperidol (0.5 mg/kg/2 ml ip)
Experimental Results:Inhibition of haloperidol-induced rigor.

---

Animal/Disease Models: Male C57BL/6J mice (23-25 g) [3]
Doses: 0.3, 1 and 3 mg/kg
Route of Administration: intraperitoneal (ip) injection, 1 hour before test
Experimental Results: Dramatically diminished mice in the tail suspension test Immobility time (Tsim Sha Tsui) increased by 24%, 41% and 48% respectively. The efficacy of MTEP used at doses of 1 and 3 mg/kg was not Dramatically different from that of imipramine (20 mg/kg, i.p.) used as a positive standard.

---

Nociception Model (CFA-induced hyperalgesia):** Rodents were treated with MTEP administered intraperitoneally (i.p.) at doses ranging from 3 to 30 mg/kg. The compound produced a dose-dependent reversal of thermal hyperalgesia induced by complete Freund's adjuvant (CFA). [1]
* **Nociception Model (Formalin and SNL):** Systemic administration of MTEP was tested in the mouse formalin pain model and the rat spinal nerve ligation (SNL) model of neuropathic pain. It reduced hyperalgesia and mechanical allodynia. [1]
* **Addiction Model (Morphine Withdrawal):** In a rat model of morphine dependence, MTEP (1-10 mg/kg, i.p.) was administered, and its effect on naloxone-precipitated withdrawal symptoms was observed. It dose-dependently inhibited withdrawal symptoms. [1]
* **Receptor Occupancy Study:** Rats and mice received an i.p. injection of MTEP (3 mg/kg). Brain samples were collected at various time points to determine the level of mGluR5 receptor occupancy using a radiolabeled tracer. [1]

---

Nociception Model (CFA-induced hyperalgesia): Rodents were treated with MTEP administered intraperitoneally (i.p.) at doses ranging from 3 to 30 mg/kg. The compound produced a dose-dependent reversal of thermal hyperalgesia induced by complete Freund's adjuvant (CFA). [1]
Nociception Model (Formalin and SNL): Systemic administration of MTEP was tested in the mouse formalin pain model and the rat spinal nerve ligation (SNL) model of neuropathic pain. It reduced hyperalgesia and mechanical allodynia. [1]
Addiction Model (Morphine Withdrawal): In a rat model of morphine dependence, MTEP (1-10 mg/kg, i.p.) was administered, and its effect on naloxone-precipitated withdrawal symptoms was observed. It dose-dependently inhibited withdrawal symptoms. [1]
Receptor Occupancy Study: Rats and mice received an i.p. injection of MTEP (3 mg/kg). Brain samples were collected at various time points to determine the level of mGluR5 receptor occupancy using a radiolabeled tracer. [1]

MTEP has a log D value of 2.1, indicating better solubility and central nervous system (CNS) penetrability compared to MPEP (log D = 3.5). [1]
The cytochrome P450 isoforms CYP1A1/2, CYP2C6, and CYP2C11 are primarily responsible for the metabolism of MTEP. Its major oxidative metabolites include a hydroxymethyl metabolite, two oxides, a thiazole-ring opened metabolite, and CO₂. [1]
Metabolism of MTEP (1 μM) in dog, monkey, and human hepatic microsomes was similar (approximately 65%). [1]
Metabolic stability studies accurately predicted in vivo clearance for MTEP in rats. After i.v. administration (2 mg/kg) and oral administration (10 mg/kg), the pharmacokinetic parameters were: plasma clearance (Clp) = 28.5 ± 2.3 mL/min/kg; volume of distribution at steady state (VDss) = 8.4 ± 1.4 L/kg; terminal half-life (t₁/₂) = 8.3 ± 0.9 h; and oral bioavailability = 16%. [1]
In rhesus monkeys, i.v. administration of MTEP (1 mg/kg) resulted in a Clp of approximately 42 mL/min/kg. [1]

At a high dose of 100 mg/kg (i.p.), MTEP showed central nervous system (CNS) side effects in rodents, as measured by impaired performance on the rotarod test and reduced exploratory locomotor activity. [1]

[1]. Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. CNS Drug Rev. 2006 Summer;12(2):149-66.

[2]. 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.

[3]. Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol Biochem Behav. 2005 Aug;81(4):901-6.

[4]. Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling. Neuropharmacology. 2004 Sep;47(3):342-50.

MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine] is a potent, highly selective, and systemically active non-competitive antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5). It was developed to have fewer off-target effects than the earlier mGluR5 antagonist MPEP, particularly concerning NMDA receptor inhibition. [1]
Its mechanism of action involves binding to an allosteric site on mGluR5, stabilizing the receptor in an inactive conformation and inhibiting the PLC/IP3/DAG second messenger cascade. [1]
Based on studies with MTEP and MPEP, mGluR5 has been implicated in various CNS disorders, including neurodegeneration, addiction, anxiety, and pain. However, studies with MTEP suggest that the neuroprotective effects previously attributed to mGluR5 antagonism with MPEP may have been partly due to MPEP's off-target NMDA receptor inhibition, as MTEP itself is not neuroprotective at selective doses. [1]

C11H9CLN2S

236.720559835434

236.017

1186195-60-7

MTEP;329205-68-7

45073467

Light yellow to yellow solid powder

3.048

1

3

2

15

253

0

YCIOJDKGCWAHLR-UHFFFAOYSA-N

InChI=1S/C11H8N2S.ClH/c1-9-13-11(8-14-9)5-4-10-3-2-6-12-7-10;/h2-3,6-8H,1H3;1H

2-methyl-4-(2-pyridin-3-ylethynyl)-1,3-thiazole;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~20 mg/mL (~84.49 mM)

Solubility in Formulation 1: 100 mg/mL (422.44 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

---

 (Please use freshly prepared in vivo formulations for optimal results.)