Neuropharmacology 38 (1999) 1493 – 1503 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist Fabrizio Gasparini a , Kurt Lingenho ¨hl a , Natacha Stoehr a , Peter J. Flor a , Micheline Heinrich a , Ivo Vranesic a , Michel Biollaz a , Hans Allgeier a , Roland Heckendorn a , Stephan Urwyler a , Mark A. Varney b , Edwin C. Johnson b , Stephen D. Hess b , Sara P. Rao b , Aida I. Sacaan b , Emily M. Santori b , Go ¨ nul Velic ¸elebi b,1 , Rainer Kuhn a, * a Noartis Pharma AG, Therapeutic Area Nerous System, CH-4002 Basle, Switzerland b SIBIA Neurosciences Incorporated, 505 Coast Bouleard South, Suite 300, La Jolla, CA 92037 -4641, USA Accepted 11 May 1999 Abstract 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 IC 50 value of 36 nM while having no agonist or antagonist activities at cells expressing the human mGlu1b receptor at concentrations up to 30 M. When tested at group II and III receptors, MPEP did not show agonist or antagonist activity at 100 M on human mGlu2, -3, -4a, -7b, and -8a receptors nor at 10 M on the human mGlu6 receptor. Electrophysiological recordings in Xenopus laeis oocytes demonstrated no significant effect at 100 M on human NMDA (NMDA1A/2A), rat AMPA (Glu3-(flop)) and human kainate (Glu6-(IYQ)) receptor subtypes nor at 10 M 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. © 1999 Elsevier Science Ltd. All rights reserved. Keywords: Metabotropic glutamate receptor; mGlu; MPEP; Non-competitive; Antagonist www.elsevier.com/locate/neuropharm 1. Introduction Metabotropic glutamate (mGlu) receptors are a het- erogeneous family of G-protein-coupled receptors linked to multiple second messengers and modulation of ion channel functions in the nervous system (Kno ¨ pfel et al., 1995a; Conn and Pin, 1997). Molecular cloning has revealed the existence of eight distinct subtypes, termed mGlu1 – mGlu8 receptors, which fall into three groups based on sequence similarities, ago- nist profiles and preferential signal transduction path- ways activated in heterologous systems. Further diversity in this receptor family is generated by splice variants in the C-terminal cytoplasmic domain. Group I receptors (mGlu1 and -5) couple to phospholipase C and up or down regulate neuronal excitability (Gereau and Conn, 1995) whereas group II (mGlu2 and -3) and group III (mGlu4, -6, -7, and -8) receptors inhibit adenylyl cyclase and reduce synaptic transmission. Metabotropic glutamate receptors have been impli- cated as potentially important therapeutic targets for a number of neurological and psychiatric disorders, al- though these studies are largely based on compounds that do not discriminate between mGlu receptor sub- types (for review see Kno ¨ pfel et al., 1995a; Conn and * Corresponding author. Tel.: +41-61-69-66378; fax: +41-61-69- 62809. E-mail address: rainer.kuhn@pharma.novartis.com (R. Kuhn) 1 Present address: Mitokor, 11494 Sorrento Valley Road, San Diego, CA 92121, USA. 0028-3908/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(99)00082-9