Synthesis and pharmacological characterisation of 2,4-Dicarboxy-pyrroles as selective non-Competitive mGluR1 antagonists

Micheli, Fabrizio; Fabio, Romano Di; Cavanni, Paolo; Rimland, Joseph M.; Capelli, Anna Maria; Chiamulera, Cristiano; Corsi, Mauro; Corti, Corrado; Donati, Daniele; Feriani, Aldo; Ferraguti, Francesco; Maffeis, Micaela; Missio, Andrea; Ratti, Emiliangelo; Paio, Alfredo; Pachera, Roberta; Quartaroli, M.; Reggiani, Angelo; Sabbatini, Fabio Maria; Trist, D.G.; Ugolini, Annarosa; Vitulli, Giovanni

doi:10.1016/s0968-0896(02)00424-8

Cited by 41 publications

(27 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2,4-Dicarboxypyrroles have been identified as a new class of highly selective noncompetitive mGlu1 antagonists (Micheli et al, 2003c). The most potent molecules of this class (e.g., GW398171X) are characterized by nanomolar concentration potency and are active both in vitro and in vivo (Micheli et al, 2003a(Micheli et al, ,b,c, 2004a.…”

Section: Noncompetitive Antagonistsmentioning

confidence: 99%

“…The most potent molecules of this class (e.g., GW398171X) are characterized by nanomolar concentration potency and are active both in vitro and in vivo (Micheli et al, 2003a(Micheli et al, ,b,c, 2004a. These compounds interact with a region near the extracellular loops of the mGlu1 receptor, although the precise binding site has not been identified (Micheli et al, 2003c).…”

Section: Noncompetitive Antagonistsmentioning

confidence: 99%

“…For example, in the model of chronic inflammation produced by the application of complete Freund's adjuvant, intrathecal pretreatment with mGlu1 receptor antagonists, such as CPCCOEt or A-841720, significantly reduces heat hyperalgesia and mechanical allodynia (Guo et al, 2004;Morè et al, 2007). Pretreatment with different classes of mGlu1 antagonists reduces nociceptive responses in the formalin test, in the carrageenan test, and in the chronic constriction injury model of inflammatory pain (Bhave et al, 2001;Zhang et al, 2002;Micheli et al, 2003c;Varty et al, 2005;Sevostianova and Danysz, 2006). However, when applied after the induction of inflammation, only LY367385 and AIDA seem to be slightly effective in reducing hyperalgesia .…”

Section: G Painmentioning

confidence: 99%

See 2 more Smart Citations

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Ferraguti

Crepaldi

Nicoletti³

2008

Pharmacol Rev

Self Cite

188

205

View full text Add to dashboard Cite

Almost 25 years after the first report that glutamate can activate receptors coupled to heterotrimeric G-proteins, tremendous progress has been made in the field of metabotropic glutamate receptors. Now, eight members of this family of glutamate receptors, encoded by eight different genes that share distinctive structural features have been identified. The first cloned receptor, the metabotropic glutamate ( mGlu) receptor mGlu1 has probably been the most extensively studied mGlu receptor, and in many respects it represents a prototypical subtype for this family of receptors. Its biochemical, anatomical, physiological, and pharmacological characteristics have been intensely investigated. Together with subtype 5, mGlu1 receptors constitute a subgroup of receptors that couple to phospholipase C and mobilize Ca(2+) from intracellular stores. Several alternatively spliced variants of mGlu1 receptors, which differ primarily in the length of their C-terminal domain and anatomical localization, have been reported. Use of a number of genetic approaches and the recent development of selective antagonists have provided a means for clarifying the role played by this receptor in a number of neuronal systems. In this article we discuss recent advancements in the pharmacology and concepts about the intracellular transduction and pathophysiological role of mGlu1 receptors and review earlier data in view of these novel findings. The impact that this new and better understanding of the specific role of these receptors may have on novel treatment strategies for a variety of neurological and psychiatric disorders is considered

show abstract

Section: Noncompetitive Antagonistsmentioning

confidence: 99%

Section: Noncompetitive Antagonistsmentioning

confidence: 99%

Section: G Painmentioning

confidence: 99%

See 1 more Smart Citation

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Ferraguti

Crepaldi

Nicoletti³

2008

Pharmacol Rev

Self Cite

188

205

View full text Add to dashboard Cite

show abstract

“…CPCCOEt (1) was the first reported mGluR1 negative allosteric modulator (Fig.1). Before 2008, only compound 4 (3,5-dimethyl PPP) (Micheli et al, 2003b) and a quinoline derivative 5 (JNJ16259685) (Lavreysen et al, 2004b;Mabire et al, 2005) had reported binding affinity (or potency) less than 20 nM (Table 1). 2,4-Dicarboxy-pyrrole ester 4 (3,, as a racemic mixture, is a highly potent and subtype-selective noncompetitive antagonist of mGluR1, having IC 50 of 16 nM at rat mGluR1 and > 1000-fold selectivity over mGluR 2, 4, and 5 (Micheli et al, 2003b).…”

Section: Allosteric Modulators and Radiotracers For Mglur1mentioning

confidence: 99%

Neuroimaging - Clinical Applications

Bright¹

2012

View full text Add to dashboard Cite

“…A recently discovered selective non-competitive mGluR1 antagonist 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198) has also been shown to bind to the CPCCOEt allosteric binding site (Kohara et al, 2005). In addition, a new class of non-competitive mGluR1 antagonists, 2,4-dicarboxypyrroles were shown to interact within the TMVII domain of the receptor (Micheli et al, 2003). In contrast, the mGluR5 selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) binds to different non-conserved residues, Pro-655 and Ser-658 in TMIII and Ala-810 in TMVII.…”

Section: Introductionmentioning

confidence: 99%

Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists

et al. 2007

View full text Add to dashboard Cite

Metabotropic glutamate receptors mGluR1 and mGluR5 stimulate phospholipase C, leading to an increased inositol triphosphate level and to Ca 2+ release from intracellular stores. Cyclothiazide (CTZ), known as a blocker of AMPA receptor desensitization, produced a non-competitive inhibition of [Ca 2+ ] i increases induced by mGluR agonists in HEK 293 cells transfected with rat mGluR1a but had no effect on the [Ca 2+ ] i signals in cells expressing rat mGluR5a. In cells expressing mGluR1, CTZ also inhibited phoshoinositide hydrolysis, as well as cAMP accumulation and arachidonic acid release induced by mGluR1 agonists, indicating a direct inhibition of the receptor and not of a particular signal transduction system. However, CTZ failed to antagonize cAMP inhibition stimulated by rat mGluR2, -3, -4, -6, -7 and -8 receptors confirming its selectivity for mGluR1. The use of chimeric receptors with substituted N-terminal domains showed that CTZ did not interact with the N-terminal mGluR1a domain. Instead, mutation analysis revealed that CTZ interacts with the Thr-815 and Ala-818 residues, located at the 7 th transmembrane domain, similarly as the mGluR1-selective antagonist CPCCOEt. In primary cultures of cerebellar granule neurons, expressing native metabotropic and ionotropic glutamate receptors, the final outcome of CTZ effects depended on its combined ability to potentiate AMPA receptors and inhibit mGluR1a receptors.

show abstract

Synthesis and pharmacological characterisation of 2,4-Dicarboxy-pyrroles as selective non-Competitive mGluR1 antagonists

Cited by 41 publications

References 52 publications

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Neuroimaging - Clinical Applications

Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists

Contact Info

Product

Resources

About