[³H]Methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine Binding to Metabotropic Glutamate Receptor Subtype 5 in Rodent Brain: In Vitro and in Vivo Characterization

Abstract

The binding of [3 H]methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (methoxymethyl-MTEP), a potent and selective antagonist for metabotropic glutamate (mGlu)5 receptors, was characterized in rat brain both in vitro and in vivo. Nonspecific binding, as defined with 10 M 2-methyl-6-(phenylethynyl)-pyridine (MPEP), was less than 10% of total binding in rat brain membranes. , 1997). There are eight mGluR subtypes, which are subdivided into three groups principally based on sequence homology, but also on signal transduction pathways and agonist selectivity (Nakanishi, 1992;Pin and Duvoisin, 1995). Group I mGluRs initiate cell responses through G q/11 protein coupling to phospholipase C and stimulation of phosphoinositide hydrolysis. In contrast, group II and group III mGluRs are negatively coupled via G i /G o to adenylyl cyclase and reduce forskolinstimulated increases in cAMP in recombinant expression systems. Group I receptors are selectively activated by dihydroxyphenylglycine (DHPG), group II receptors can be stimulated by (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine and (ϩ)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740), and group III receptors are selectively stimulated by L-(ϩ)-2-amino-4-phosphonobutyric acid and (R,S)-4-phosphonophenylglycine (Schoepp et al., 1999).Group I mGluRs include the mGlu1 and mGlu5 subtypes. These two receptors exhibit a regional pattern of expression in the central nervous system, suggesting distinct, functional roles for each receptor (Spooren et al., 2001). For example, expression of mGlu5 receptor protein is high-to-moderate in frontal cortex, caudate putamen, nucleus accumbens, olfacArticle, publication date, and citation information can be found at

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

“…The selectivity of MPEP action on mGluR5 has recently been questioned since it could act as an allosteric potentiator of mGluR4 (Mathiesen et al, 2003) and exert its effects through this group III mGluRs subtype. Although this nonselective action cannot be ruled out the range of doses of MPEP below 10 mM used in the present study possess a better affinity for mGluR5 than for mGluR4 (Anderson et al, 2002). Nevertheless, as previously shown (Breysse et al, 2002) the range of doses alleviating 6-OHDA-induced deficits without inducing side effects is relatively narrow.…”

Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors

“…33 Systemic administration of the more specific Group II mGluR2/3 agonist LY314582, or its racemate ( þ )-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) 34 did not alter PPI alone nor did it alter the effects of the NMDA antagonist PCP. 35,36 In contrast, while the mGluR5 antagonist MPEP had no effect on PPI by itself even when administered at doses reported to attain at least 90% receptor occupancy, 29,[36][37][38] it was shown to exacerbate the PPI deficit produced by PCP administration. 29,36 Thus, although MPEP alone does not appear to disrupt PPI in rodents, the influence of this mGluR5 antagonist on PPI in PCP-treated animals is consistent with the phenotypic difference in PPI in the mGluR5 KO mice.…”

The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety

“…In vivo receptor occupancy of MTEP was determined using methods described previously (Anderson et al, 2002). In brief, rats were dosed i.p.…”