A novel class of antagonists for metabotropic glutamate receptors, 7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylates
The synthesis of 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates (4a-c), highly potent antagonists for a phospholipase C-linked metabotropic glutamate receptor, mGluR1, is described.
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Targeting mGluR group III for the treatment of neurodegenerative diseases
2023, Biomedicine and PharmacotherapyNeuropharmacological Insight from Allosteric Modulation of mGlu Receptors
2019, Trends in Pharmacological SciencesCitation Excerpt :In functional assays such as those that measure calcium mobilization, the effect of a PAM is often to induce a leftward shift of the agonist concentration–response curve, while a NAM will decrease the maximal effect of the response. The first allosteric modulator of mGlu receptors identified was the mGlu1 NAM, CPCCOEt [6]; a compound that was shown to inhibit mGlu1 receptor signaling without affecting glutamate binding [7]. This was followed shortly by the discovery of the first selective mGlu5 NAMs, SIB-1757 and SIB-1893 [8].
Allosteric modulators targeting GPCRs
2019, GPCRs: Structure, Function, and Drug DiscoveryMolecular insights into allosteric modulation of Class C G protein-coupled receptors
2017, Pharmacological ResearchCitation Excerpt :The clinical success of CaSR PAMs provides the promise that allosteric modulators of other Class C GPCRs will offer new therapeutics. Although the mGlu1 NAM, CPCCOEt, was the first mGlu allosteric ligand disclosed [191,192], the mGlu5 NAM, fenobam, was discovered much earlier [193]; however, its target was not elucidated until many years later [194]. Intensive directed discovery efforts have subsequently yielded selective and pharmacologically diverse allosteric ligands for the majority of mGlu family members (Table 1).
Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain
2015, European Journal of Medicinal ChemistryCitation Excerpt :Additionally, suppressing the activation of mGluR1 via genetic knockdown or small molecule antagonists attenuated nociceptive responses in animal models of pain [19–25] indicating that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain [26,27]. Since the first non-competitive antagonist of mGluR1, CPCCOEt, was identified [28,29], many small molecule antagonists were developed and utilized to establish the location and structure of the allosteric binding site [30]. Furthermore, with the help of the structural information, a number of highly potent allosteric antagonists of mGluR1 have been reported to date, and several examples are shown in Fig. 1.