2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist.
In the present paper we describe 2-methyl-6-(phenylethynyl)-pyridine (MPEP) as a potent, selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGlu5). At the human mGlu5a receptor expressed in recombinant cells, MPEP completely inhibited quisqualate-stimulated phosphoinositide (PI) hydrolysis with an IC50 value of 36 nM while having no agonist or antagonist activities at cells expressing the human mGlu1b receptor at concentrations up to 30 microM. When tested at group II and III receptors, MPEP did not show agonist or antagonist activity at 100 microM on human mGlu2, -3, -4a, -7b, and -8a receptors nor at 10 microM on the human mGlu6 receptor. Electrophysiological recordings in Xenopus laevis oocytes demonstrated no significant effect at 100 microM on human NMDA (NMDA1A/2A), rat AMPA (Glu3-(flop)) and human kainate (Glu6-(IYQ)) receptor subtypes nor at 10 microM on the human NMDA1A/2B receptor. In rat neonatal brain slices, MPEP inhibited DHPG-stimulated PI hydrolysis with a potency and selectivity similar to that observed on human mGlu receptors. Furthermore, in extracellular recordings in the CA1 area of the hippocampus in anesthetized rats, the microiontophoretic application of DHPG induced neuronal firing that was blocked when MPEP was administered by iontophoretic or intravenous routes. Excitations induced by microiontophoretic application of AMPA were not affected.
Gasparini
F
F
Novartis Pharma AG, Therapeutic Area Nervous System, Basle, Switzerland.
Lingenhöhl
K
K
Stoehr
N
N
Flor
P J
PJ
Heinrich
M
M
Vranesic
I
I
Biollaz
M
M
Allgeier
H
H
Heckendorn
R
R
Urwyler
S
S
Varney
M A
MA
Johnson
E C
EC
Hess
S D
SD
Rao
S P
SP
Sacaan
A I
AI
Santori
E M
EM
Veliçelebi
G
G
Kuhn
R
R
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009865:Oocytes / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D016318:Quisqualic Acid / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013462:Sulfur Radioisotopes; D014162:Transfection; D014982:Xenopus laevis
D018691:Excitatory Amino Acid Antagonists; D010716:Phosphatidylinositols; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D013462:Sulfur Radioisotopes; C113897:metabotropic glutamate receptor 6; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008734:Methoxyhydroxyphenylglycol; C121465:6-methyl-2-(phenylethynyl)pyridine; D016318:Quisqualic Acid; D000242:Cyclic AMP; D018021:Lithium Chloride; C010117:3,4-dihydroxyphenylglycol