共查询到20条相似文献,搜索用时 15 毫秒
1.
Pinkerton AB Cube RV Hutchinson JH James JK Gardner MF Schaffhauser H Rowe BA Daggett LP Vernier JM 《Bioorganic & medicinal chemistry letters》2004,14(23):5867-5872
We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead. 相似文献
2.
Pinkerton AB Cube RV Hutchinson JH Rowe BA Schaffhauser H Zhao X Daggett LP Vernier JM 《Bioorganic & medicinal chemistry letters》2004,14(21):5329-5332
We have identified and synthesized a series of aryl-tetrazoyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation led to the discovery of 22 (EC(50)=93nM, 128% potentiation). 相似文献
3.
Bonnefous C Vernier JM Hutchinson JH Gardner MF Cramer M James JK Rowe BA Daggett LP Schaffhauser H Kamenecka TM 《Bioorganic & medicinal chemistry letters》2005,15(19):4354-4358
We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency and the brain to plasma ratio of the initial lead led to the discovery of 5 and 23 (EC50=111 and 5 nM, respectively). 相似文献
4.
János Galambos Gábor Wágner Katalin Nógrádi Attila Bielik László Molnár Amrita Bobok Attila Horváth Béla Kiss Sándor Kolok József Nagy Dalma Kurkó Mónika L. Bakk Mónika Vastag Katalin Sághy István Gyertyán Krisztina Gál István Greiner Zsolt Szombathelyi György M. Keserű György Domány 《Bioorganic & medicinal chemistry letters》2010,20(15):4371-4375
Hit-to-lead optimization of a HTS hit led to new carbamoyloxime derivatives. After identification of an advanced hit (8d) the CYP enzyme inhibitory activity of this class of compounds was successfully eliminated. Systematic exploration of different parts of the advanced hit led us to some promising lead compounds with mGluR5 affinities comparable to that of MPEP. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2020,30(13):127212
This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu2/4 heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu2 PAM at one terminus and an mGlu4 PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu2 and mGlu4 but also in cells expressing mGlu2 or mGlu4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu2/2 homodimer over heterodimeric mGlu2/4 or homomeric mGlu4/4. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs. 相似文献
6.
Hu E Chua PC Tehrani L Nagasawa JY Pinkerton AB Rowe BA Vernier JM Hutchinson JH Cosford ND 《Bioorganic & medicinal chemistry letters》2004,14(20):5071-5074
Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure-activity-relationship investigations are discussed. 相似文献
7.
Büttelmann B Peters JU Ceccarelli S Kolczewski S Vieira E Prinssen EP Spooren W Schuler F Huwyler J Porter RH Jaeschke G 《Bioorganic & medicinal chemistry letters》2006,16(7):1892-1897
Optimisation of affinity, chemical stability, metabolic stability and solubility led from a chemically labile HTS hit 1 to mGlu5 receptor antagonists (24-26) with high affinity for the allosteric MPEP binding site, improved microsomal metabolic stability and anxiolytic-like activity in vivo as assessed by the Vogel conflict drinking test. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(12):2693-2698
Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu2 and mGlu3, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu2/mGlu3 NAMs, with excellent selectivity versus the other mGluRs. 相似文献
9.
Schober DA Gill MB Yu H Gernert DL Jeffries MW Ornstein PL Kato AS Felder CC Bredt DS 《The Journal of biological chemistry》2011,286(15):13134-13142
AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [(3)H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [(3)H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [(3)H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [(3)H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites. 相似文献
10.
Eric Vieira Jörg Huwyler Synèse Jolidon Frédéric Knoflach Vincent Mutel Jürgen Wichmann 《Bioorganic & medicinal chemistry letters》2009,19(6):1666-1669
Small molecule mGluR1 enhancers, which are 9H-xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides, have been previously reported. Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides with improved pharmacokinetic properties have been designed and synthesized as useful pharmacological tools for the study of the physiological roles mediated by mGlu1 receptors. The synthesis and the structure–activity relationship of this class of positive allosteric modulators of mGlu1 receptors will be discussed in detail. 相似文献
11.
Metabotropic glutamate receptors (mGlus) are G-protein-coupled receptors playing an important role in the central nervous system (CNS). Recently, mGlus have been identified in peripheral tissues, and aberrant expression or inhibition of the receptors functions in the development of certain cancers. However, the correlation of mGlu activity with hepatocellular carcinoma (HCC) remains unknown. In this study, we analyzed the effects of inhibiting mGlu5 activity in hepatocarcinoma cell lines and a xenograft model. Inactivation of mGlu5 with 2-Methyl-6-(phenylethyl)-pyridine (MPEP), a specific antagonist of the receptor, caused inhibition of cell growth, migration, and invasion of HepG2 and Bel-7402 cells, assessed by MTT assay, ATP production, wound healing, and Boyden chamber assay, respectively. Moreover, inhibition of tumor growth and the potential metastasis of hepatocellular carcinoma were also found in nude mice. Furthermore, mGlu5-mediated extracellular signal-regulated kinase (ERK) phosphorylation has been found to be partially involved in cell growth and migration, as detected by stimulation of (S)-3,5-Dihydroxyphenylglycine (DHPG), an agonist of the receptor, and blockage of MPEP and U0126, an inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK). These data indicate that inhibiting the activity of mGlu5 has the molecular potential to suppress oncogenic actions by blocking downstream effector molecules. The study suggests that mGlu5 activity may contribute to understanding the development of HCC. 相似文献
12.
Springer SK Woodin KS Berry V Boezio AA Cao L Clarkin K Harmange JC Hierl M Knop J Malmberg AB McDermott JS Nguyen HQ Waldon D Albrecht BK McDonough SI 《Bioorganic & medicinal chemistry letters》2008,18(20):5643-5647
The synthesis and structure-activity relationship of a series of carbamate potentiators of alpha4beta2 nAChR is reported herein. These compounds were highly selective for alpha4beta2 over other nAChR subtypes. In addition, compounds increased the response of alpha4beta2 nAChRs to acetylcholine, as measured with patch-clamp electrophysiology. 相似文献
13.
Summary. Numerous pharmacological data indicate involvement of glutamate, the major excitatory neurotransmitter in the brain, in the
pathophysiology of several neuropsychiatric disorders. It was shown in the preclinical studies that compounds which can reduce
the excess of glutamate release (for example group III metabotropic receptors agonists) possess potential therapeutic properties.
Thus we focused our interests on (−)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), which is a positive
allosteric modulator of mGlu4 receptor. We examined the potential antidepressant-like activity of PHCCC after injection into
the brain ventricles alone, or together with (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I), a nonselective
group III mGlu receptor agonist, using the forced swimming test (FST) in rats. We found that ACPT-I induced a dose dependent
antidepressant-like effect in FST, which was blocked by an antagonist of group III mGlu receptors (RS)-alpha-cyclopropyl-4-phosphonophenylglycine
(CPPG). PHCCC injected intracerebroventricular was not effective, however when the compound was administered together with
non-effective dose of ACPT-I, a profound antidepressant-like activity in FST was demonstrated. This effect was reversed by
CPPG, group III mGlu receptors antagonist. Results of our studies indicate that a combined administration positive allosteric
modulation of mGlu4 receptor and agonists of group III mGlu receptors may be a promising target in the future treatment of
depressive disorder. 相似文献
14.
Julie Perroy Sylvain Richard Joel Nargeot Joel Bockaert Laurent Fagni 《The Journal of biological chemistry》2002,277(2):1223-1228
G protein-coupled receptors mobilize neuronal signaling cascades which until now have not been shown to depend on the state of membrane depolarization. Thus we have previously shown that the metabotropic glutamate receptor type 7 (mGlu7 receptor) blocks P/Q-type Ca(2+) channels via activation of a G(o) protein and PKC, in cerebellar granule cells. We show here that the transient depolarizations used to evoke the studied Ca(2+) current were indeed permissive to activate this pathway by a mGlu7 receptor agonist. Indeed, sustained depolarization to 0 mV was sufficient to inhibit P/Q-type Ca(2+) channels. This effect involved a conformational change in voltage-gated sodium channel independently of Na(+) flux, activation of a pertussis toxin-sensitive G-protein, inositol trisphosphate formation, intracellular Ca(2+) release, and PKC activity. Subliminal sustained membrane depolarization became efficient in inducing inositol trisphosphate formation, release of intracellular Ca(2+) and in blocking Ca(2+) channels, when applied concomitantly with the mGlu7a receptor agonist, d,l-aminophosphonobutyrate. This synergistic effect of membrane depolarization and mGlu7 receptor activation provides a mechanism by which neuronal excitation could control action of the mGlu7 receptor in neurons. 相似文献
15.
Anna Stankiewicz Katarzyna Kaczorowska Ryszard Bugno Aneta Kozio Maria H. Paluchowska Grzegorz Burnat Barbara Chrucicka Paulina Chorobik Piotr Braski Joanna M. Wieroska Beata Duszyska Andrzej Pilc Andrzej J. Bojarski 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):211
Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282–656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM . ADX88178相似文献
16.
17.
Metabotropic glutamate mGlu5 receptors have been implicated in the regulation of seizures and have been suggested as a target against which discovery of novel anticonvulsants may be possible. However, the experimental literature is not consistent in reporting anticonvulsant efficacy of mGlu5 receptor antagonists. Additional assessment of this target was approached in the present study by comparing convulsions in wild-type (WT) and mGlu5 receptor null (knockout or KO) mice. Chemically induced seizures induced by a variety of mechanisms including pentylenetetrazole, N-methyl-d-aspartic acid (NMDA), cocaine, kainic acid, aminophylline, 4-aminopyridine, strychnine, and nicotine did not differentially increase clonic, clonic/tonic, or lethality in WT vs. mGlu5 receptor KO mice. The mGlu5 receptor antagonist 3-[(2-Methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) did not significantly prevent seizures induced by NMDA; in contrast, the uncompetitive NMDA receptor antagonist, dizocilpine, significantly prevented NMDA-induced seizures and lethality in both WT and KO mice. The present findings do not support the idea that mGlu5 receptors play as important a role in seizure control as previously speculated. 相似文献
18.
代谢型谷氨酸受体5(metabotropic glutamate receptors 5, mGlu 5)在神经系统的多种病理生理过程中发挥重要作用. mGlu5与肝细胞癌的发生发展关系密切,其抑制剂2-甲基-6-(苯乙基)-吡啶(2-methyl-6-(phenylethyl)-pyridine, MPEP)能够促进肝癌细胞凋亡,抑制肝癌细胞的迁移.在此基础上,进一步探讨了MPEP与肝癌细胞增殖之间的关系.结果显示:在无血清和有血清的条件下,MPEP均能显著降低肝癌细胞HepG2的细胞活力.同时发现,有血清条件下MPEP能使HepG2细胞周期停滞在G1 期,显著降低HepG2细胞的DNA合成能力和克隆形成能力,并能下调细胞增殖信号ERK 通路的活性.该研究结果为进一步认识MPEP对肝癌细胞的抑制作用提供了新的实验证据. 相似文献
19.
Stephen P. East Samantha Bamford Matthias G.A. Dietz Christian Eickmeier Adam Flegg Boris Ferger Mark J. Gemkow Ralf Heilker Bastian Hengerer Adrian Kotey Pui Loke Gerhard Schänzle Hans-Dieter Schubert John Scott Mark Whittaker Mildred Williams Przemyslaw Zawadzki Kai Gerlach 《Bioorganic & medicinal chemistry letters》2010,20(16):4901-4905
A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure–activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented. 相似文献
20.
Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18‐1 下载免费PDF全文
Christian Kortleven Vincent Huson Tim Kroon Josta T Kevenaar Desiree Schut Ingrid Saarloos Joost P Hoetjes Heidi de Wit Oliver Stiedl Sabine Spijker Ka Wan Li Huibert D Mansvelder August B Smit Lennart Niels Cornelisse Matthijs Verhage Ruud F Toonen 《The EMBO journal》2016,35(11):1236-1250
Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal‐regulated kinase (ERK) that mediates CB1R‐ and mGluR2/3‐induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock‐induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18‐1. Mimicking constitutive phosphorylation of Munc18‐1 results in a drastic decrease in synaptic transmission. ERK‐mediated phosphorylation of Munc18‐1 ultimately leads to degradation by the ubiquitin–proteasome system. Conversely, preventing ERK‐dependent Munc18‐1 phosphorylation increases synaptic strength. CB1R‐ and mGluR2/3‐induced synaptic inhibition and depolarization‐induced suppression of excitation (DSE) are reduced upon ERK/MEK pathway inhibition and further reduced when ERK‐dependent Munc18‐1 phosphorylation is blocked. Thus, ERK‐dependent Munc18‐1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity. 相似文献