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 metabot ropic glutamate receptor subtype 5 (mGlu5). At the human mGlu5a receptor ex pressed in recombinant cells, MPEP completely inhibited quisqualate-stimula ted phosphoinositide (PI) hydrolysis with an IC50 value of 36 nM while havi ng no agonist or antagonist activities at cells expressing the human mGlu1b receptor at concentrations up to 30 mu M. When tested at group II and III receptors, MPEP did not show agonist or antagonist activity at 100 mu M on human mGlu2, -3, -4a, -7b, and -8a receptors nor at 100 mu M on the human m Glu6 receptor. Electrophysiological recordings in Xenopus laevis oocytes de monstrated no significant effect at 100 mu M on human NMDA (NMDA1A/2A), rat AMPA (Glu3-(flop)) and human kainate (Glu6-(IYQ)) receptor subtypes nor at 100 mu M on the human NMDA1A/2B receptor. In rat neonatal brain slices, MP EP inhibited DHPG-stimulated PI hydrolysis with a potency and selectivity s imilar to that observed on human mGlu receptors. Furthermore, in extracellu lar recordings in the CAI area of the hippocampus in anesthetized rats, the microiontophoretic application of DHPG induced neuronal firing that was bl ocked when MPEP was administered by iontophoretic or intravenous routes. Ex citations induced by microiontophoretic application of AMPA were not affect ed. (C) 1999 Elsevier Science Ltd. All rights reserved.