Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain

doi:10.1016/j.bmcl.2011.12.131

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 4, 15 February 2012, Pages 1575-1578

https://doi.org/10.1016/j.bmcl.2011.12.131 Get rights and content

Abstract

A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.

Graphical abstract

References and notes (9)

F. Gasparini et al.
Curr. Opin. Pharm.
(2002)
V. Neugebauer
Pain
(2002)
S.H. Kim et al.
Pain
(1992)

There are more references available in the full text version of this article.

Cited by (22)

3-Amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carbonitrile: A fluorescent molecule that induces differentiation in PC12 cells
2024, Bioorganic and Medicinal Chemistry
Neural differentiation is triggered by the activation of multiple signaling pathways initiated by various neurotrophic factors. An elucidation of these mechanisms is anticipated to facilitate the prevention of diseases and the development of novel therapeutic approaches. Alternative small-molecule inducers for neuroscience studies are required instead of protein-based reagents for more efficient and convenient experiments. We demonstrated that small molecules of thieno[2,3-b]pyridine derivatives that induce neural differentiation, compounds 3a and 9a in particular, exhibited significant neuritogenic activity in rat pheochromocytoma (PC12) cells. Moreover, 3a displayed pronounced fluorescence and a discernible Stokes shift. Furthermore, the outcome of the experiment conducted on the NGF-insensitive clones of rat PC12 cells, and the results of the intercellular uptake analyses suggested that the 3a-mediated activation of neural differentiation occurred independently of the TrkA receptor. Therefore, 3a portrays potential applicability both as a small molecule reagent to replace novel neurotrophic factors and as a potent fluorescent reagent for various techniques, including bioimaging.
DIPEA catalyzed step-by-step synthesis and photophysical properties of thieno[2,3-b]pyridine derivatives
2019, Tetrahedron
Citation Excerpt :
The only exception is the single work reported on electronic absorption, excitation and fluorescence properties of two compounds – 3-amino-4,5,6-trimethyl-thieno[2,3-b]pyridin-2-yl(phenyl)methanone and 3-amino-5,6,7,8-tetrahydro-thieno[2,3-b]quinolin-2-yl)(phenyl)methanone [32]. We consider that spectral-fluorescent studies of the thieno[2,3-b]pyridine derivatives are extremely important due to the presence of this motif in various biologically active molecules [1–18]. Therefore, the use of these molecules as fluorescent labels and probes could reveal a mechanism of their biological action.
A series of novel 5,6-disubstituted ethyl 3-amino-4-cyanothieno[2,3-b]pyridine-2-carboxylates was synthesized. The reaction conditions were thoroughly studied and intermediate ethyl 2-((3,4-dicyanopyridin-2-yl)thio)acetates were successfully isolated in good yields. For all synthesized compounds, spectral-fluorescent properties were carefully investigated and correlation thereof with chemical structure was found.
In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis
2017, Neuropharmacology
Citation Excerpt :
On the other hand, mGluR1 knocking down seems to play a significant role in motor function preservation. Accordingly, mGluR1 is implicated in the regulation of motor and sensory functions in different brain regions (Swanson and Kalivas, 2000; Nakao et al., 2007; Bennett et al., 2012), while mGluR5 has not been associated to motor control, being instead involved in synaptic plasticity, learning, memory and cognition process (Naie and Manahan-Vaughan, 2004; Simonyi et al., 2005). Although the functional interaction between mGluR1 and mGluR5 has been extensively reported (Benquet et al., 2002; Fazal et al., 2003; Musante et al., 2008; Sevastyanova and Kammermeier, 2014), the existence of mGluR1/mGluR5 heterodimers has been demonstrated only recently, using a fluorescence energy transfer assay (Doumazane et al., 2011) or by proteomic and super resolution imaging strategies (Pandya et al., 2016).
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to loss of upper and lower motor neurons (MNs). The mechanisms of neuronal death are largely unknown, thus prejudicing the successful pharmacological treatment. One major cause for MN degeneration in ALS is represented by glutamate(Glu)-mediated excitotoxicity. We have previously reported that activation of Group I metabotropic Glu receptors (mGluR1 and mGluR5) at glutamatergic spinal cord nerve terminals produces abnormal Glu release in the widely studied SOD1^G93A mouse model of ALS. We also demonstrated that halving mGluR1 expression in the SOD1^G93A mouse had a positive impact on survival, disease onset, disease progression, and on a number of cellular and biochemical readouts of ALS. We generated here SOD1^G93A mice with reduced expression of mGluR5 (SOD1^G93AGrm5^−/+) by crossing the SOD1^G93A mutant mouse with the mGluR5 heterozigous Grm5^−/+ mouse. SOD1^G93AGrm5^−/+ mice showed prolonged survival probability and delayed pathology onset. These effects were associated to enhanced number of preserved MNs, decreased astrocyte and microglia activation, reduced cytosolic free Ca²⁺ concentration, and regularization of abnormal Glu release in the spinal cord of SOD1^G93AGrm5^−/+ mice. Unexpectedly, only male SOD1^G93AGrm5^−/+ mice showed improved motor skills during disease progression vs. SOD1^G93A mice, while SOD1^G93AGrm5^−/+ females did not. These results demonstrate that a lower constitutive level of mGluR5 has a significant positive impact in mice with ALS and support the idea that blocking Group I mGluRs may represent a potentially effective pharmacological approach to the disease.
Activation of mGluR1 contributes to neuronal hyperexcitability in the rat anterior cingulate cortex via inhibition of HCN channels
2016, Neuropharmacology
Neuronal hyperexcitability in the anterior cingulate cortex (ACC) is considered as one of the most important pathological changes responsible for the chronification of neuropathic pain. However, the underlying mechanisms remain elusive. In the present study, we investigated the possible mechanisms using a rat model of chronic constriction injury (CCI) to the sciatic nerve. We found a substantial decrease in hyperpolarization-activated/cyclic nucleotide-gated (HCN) currents in layer 5 pyramidal neurons (L5 PNs) in ACC slices, which dramatically increased the excitability of these neurons. This effect could be mimicked in sham slices by activating group 1 metabotropic glutamate receptors, and be blocked in CCI slices by inhibiting metabotropic glutamate receptor subtype 1 (mGluR1). Next, the inhibition of HCN currents was reversed by a protein kinase C (PKC) inhibitor, followed by a reduced neuronal hyperexcitability. Furthermore, HCN channel subtype 1 (HCN1) level was significantly reduced after CCI, whereas mGluR1 level increased. These changes were mainly observed in L5 of the ACC, where HCN1 and mGluR1 were highly colocalized. For behavioral tests, intra-ACC microinjection of mGluR1-shRNA suppressed the CCI-induced behavioral hypersensitivity, particularly thermal hyperalgesia, but not aversive behavior, and this effect was attenuated by the pre-blockade of HCN channels. Taken together, the neuronal hyperexcitability of ACC L5 PNs likely results from an upregulation of mGluR1 and a downstream pathway involving PKC activation and a downregulation of HCN1 in the early phase of neuropathic pain. These alterations may at least in part contribute to the development of behavioral hypersensitivity in CCI rats.
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 Chemistry
Citation Excerpt :
Particularly, many studies suggested that mGluR1 is located in the brain regions including dorsal root ganglia, spinal cord, thalamus, and cerebral cortex, most of which are known to be involved in pain sensing [15–18]. 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].
Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.
Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: A potential treatment for neuropathic pain
2015, Bioorganic and Medicinal Chemistry Letters
Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.

View all citing articles on Scopus

View full text

Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain

Abstract

Graphical abstract

Curr. Opin. Pharm.

Pain

Pain