Description
Glutamate, the major excitatory neurotransmitter in the brain, acts on both ionotropic and metabotropic glutamate receptors. Excessive metabotropic glutamate receptor (mGluR) transmission has been linked to epilepsy, ischemia, pain, anxiety, and depression. Eight subtypes (1-
8) and multiple splice variants of the mGluR have been identified and grouped based on their pharmacological properties. Group I mGluRs (subtypes 1 and 5) activate the phosphatidyl inositol pathway, while Group II (2 and 3) and Group III (4, 6, 7 and 8) inhibit adenylyl cyclase. MPEP is a potent, highly selective non-
competitive antagonist at the mGlu5a receptor subtype (IC
50 = 36 nM) while having no agonist or antagonist activities at the mGlu1b receptor at concentrations up to 30 μM. MPEP is centrally active following systemic administration
in vivo, inducing anxiolytic-
like effects in rodent models of anxiety and depression when administered at 1-
30 mg/kg. MPEP has also been reported as a positive allosteric modulator of mGluR4 at μM concentrations.
Uses
MPEP is a potent and highly selective non-competitive mGlu5a receptor antagonist (1,2). It is also a positive allosteric modulator at mGlu4 receptors.MPEP exhibits anxiolytic and antidepressant properties that may be applicable for treating schizophrenia (3).
Uses
Glutamate, the major excitatory neurotransmitter in the brain, acts on both ionotropic and metabotropic glutamate receptors. Excessive metabotropic glutamate receptor (mGluR) transmission has been linked to epilepsy, ischemia, pain, anxiety, and depression. Eight subtypes (1-8) and multiple splice variants of the mGluR have been identified and grouped based on their pharmacological properties. Group I mGluRs (subtypes 1 and 5) activate the phosphatidyl inositol pathway, while Group II (2 and 3) and Group III (4, 6, 7 and 8) inhibit adenylyl cyclase. MPEP is a potent, highly selective non-competitive antagonist at the mGlu5a receptor subtype (IC50 = 36 nM) while having no agonist or antagonist activities at the mGlu1b receptor at concentrations up to 30 μM. MPEP is centrally active following systemic administration in vivo, inducing anxiolytic-like effects in rodent models of anxiety and depression when administered at 1-30 mg/kg. MPEP has also been reported as a positive allosteric modulator of mGluR4 at μM concentrations.
Definition
ChEBI: A methylpyridine that coinsists of 2-methylp[yridine bearing an additional phenylethynyl group at position 6. Potent and highly selective non-competitive antagonist at the mGlu5 receptor subtype (IC50 = 36 nM) and
positive allosteric modulator at mGlu4 receptors. Centrally active following systemic administration in vivo. Reverses mechanical hyperalgesia in the inflamed rat hind paw.
General Description
GRIN2B (glutamate ionotropic receptor NMDA type subunit 2B) codes for N-methyl d-aspartate receptor subtype 2B (GluN2B). It belongs to the N-methyl-D-aspartate receptor (NMDAR) gene family. It is located on chromosome 12p13.1.
Biochem/physiol Actions
GRIN2B (glutamate ionotropic receptor NMDA type subunit 2B) plays an important role in the growth of neurons and is highly essential for learning and memory. GRIN2B mutation is associated with neuropsychiatric and developmental disorders like schizophrenia, Parkinson′s disease and bipolar disorder. MPEP (2-methyl-6-(phenylethynyl)pyridine?hydrochloride) is used to treat Alzheimer′s disease (AD).
in vitro
in recombinant expressed cells human mglu5a receptor, mpep inhibited quisqualate-stimulated phosphoinositide hydrolysis completely with an ic50 value of 36 nm whereas with no agonist or antagonist activities at cells expressing the human mglu1b receptor. mpep did not show agonist or antagonist activity on human mglu2, -3, -4a, -7b, and -8a receptors [1].
in vivo
in rat neonatal brain slices, mpep inhibited dhpg-stimulated phosphoinositide hydrolysis with a potency and selectivity similar to that observed on human mglu receptors. moreover, in extracellular recordings in the hippocampus ca1 area of anesthetized rats, the microiontophoretic application of dhpg induced neuronal firing that was blocked when mpep was administered [1].
References
1) Gasparini et al. (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective, and systemically active mGlu5 receptor antagonist; Neuropharmacology 38 1493
2) Mathiesen et al. (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4(hmGlu4) by SIB-1893 and MPEP; Br. J . Pharmacol. 138 1026
3) Morin et al. (2010) Effect of metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys; Neuropharmacology 58 981
4) Morin et al. (2013) MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates; Neuropharmacology 66 355
5) Michalon et al. (2012) Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice; Neuron 74 49
6) Mihov and Hasler (2016) Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window; Int. J. Neuropsychopharmacol. 19 pyw002
