共查询到20条相似文献,搜索用时 31 毫秒
1.
This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu 2/4 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 mGlu 2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu 2 PAM at one terminus and an mGlu 4 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 mGlu 2 and mGlu 4 but also in cells expressing mGlu 2 or mGlu 4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu 2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu 2/2 homodimer over heterodimeric mGlu 2/4 or homomeric mGlu 4/4. 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
2.
Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of l-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold’s unique group II selectivity that explores the subtle distance differences between the α-carbon of l-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu 2). 相似文献
3.
Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu 4 receptor positive allosteric modulatory activity (EC 50 = 282–656 nM). Selectivity screening revealed that they were devoid of activity at mGlu 1, mGlu 2 and mGlu 5 receptors, but modulated mGlu 7 and mGlu 8 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 mGlu 4 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 mGlu 4 PAM {"type":"entrez-protein","attrs":{"text":"ADX88178","term_id":"323512724"}}ADX88178. 相似文献
4.
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu 5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu 5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu 5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism. 相似文献
5.
Development of SAR in an aryl ether series of mGlu 5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu 5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu 5 antagonists as well as clinically efficacious anxiolytics. 相似文献
6.
Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) G protein coupled receptors. Docking of
agonists and antagonists to CB 1 and CB 2 cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch and its possible participation
in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite
transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB 1 and CB 2 receptor models were constructed based on the adenosine A 2A receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor
conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type
matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of β 2AR, the ( R,R) and ( S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving
the same average position of ligands in the binding site. The ( S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes
may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions.
However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect
the process of activation. 相似文献
7.
Herein we report the design and synthesis of a series of substituted pyrazolo[1,5- a]quinazolin-5(4 H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu 2 and mGlu 3, 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(4 H)-one (10b), were discovered with potent in vitro activity as dual mGlu 2/mGlu 3 NAMs, with excellent selectivity versus the other mGluRs. 相似文献
8.
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu 5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu 5 PAM chemotype. 相似文献
9.
Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies. 相似文献
10.
mGlu1 and mGlu5 metabotropic glutamate receptors are expressed in the vertebrate retina, and are co-localized in some retinal neurons. It is believed that both receptors are coupled to polyphosphoinositide (PI) hydrolysis in the retina and their function may diverge in some cells because of a differential engagement of downstream signaling molecules. Here, we show that it is only the mGlu1 receptor that is coupled to PI hydrolysis in the retina. We used either bovine retinal slices or intact mouse retinas challenged with the mixed mGlu1/5 receptor agonist, DHPG. In both models, DHPG-stimulated PI hydrolysis was abrogated by the selective mGlu1 receptor antagonist, JNJ16259685, but was insensitive to the mGlu5 receptor antagonist, MPEP. In addition, the PI response to DHPG was unchanged in the retina of mGlu5?/? mice but was abolished in the retina of crv4 mice lacking mGlu1 receptors. Stimulation of the mitogen-activated protein kinase pathway by DHPG in intact mouse retinas were also entirely mediated by mGlu1 receptors. Our data provide the first example of a tissue in which a biochemically detectable PI response is mediated by mGlu1, but not mGlu5, receptors. Hence, bovine retinal slices might be used as a model for the functional screening of mGlu1 receptor ligands. In addition, the mGlu1 receptor caters the potential as a drug target in the experimental treatment of degenerative disorders of the retina. 相似文献
11.
Development of SAR in an aryl ether series of mGlu 5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu 5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu 5 antagonists and other anxiolytics, produced dose proportional effects. 相似文献
12.
A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu 5). This Letter describes the SAR of this series and the profile of selected compounds in selectivity and radioligand binding assays. 相似文献
13.
NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine-binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glycine sites of GluN1 and GluN3 subunits would be valuable pharmacological tools for studies on the function and physiological roles of NMDA receptor subtypes. In a virtual screening for antagonists that exploit differences in the orthosteric binding site of GluN1 and GluN3 subunits, we identified a novel glycine site antagonist, 1-thioxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (TK40). Here, we show by Schild analysis that TK40 is a potent competitive antagonist with Kb values of 21–63 n m at the GluN1 glycine-binding site of the four recombinant GluN1/N2A-D receptors. In addition, TK40 displayed >100-fold selectivity for GluN1/N2 NMDA receptors over GluN3A- and GluN3B-containing NMDA receptors and no appreciable effects at AMPA receptors. Binding experiments on rat brain membranes and the purified GluN1 ligand-binding domain using glycine site GluN1 radioligands further confirmed the competitive interaction and high potency. To delineate the binding mechanism, we have solved the crystal structure of the GluN1 ligand-binding domain in complex with TK40 and show that TK40 binds to the orthosteric binding site of the GluN1 subunit with a binding mode that was also predicted by virtual screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an α-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design. 相似文献
14.
This Letter describes a chemical lead optimization campaign directed at a weak mGlu 5 NAM discovered while developing SAR for the mGlu 5 PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu 5 NAMs, mGlu 5 PAMs as well as mGlu 5 partial antagonists. 相似文献
15.
The available evidence for receptor–receptor interactions between adenosine A 2A, dopamine D 2, cannabinoid CB 1, and metabotropic glutamate mGlu 5 receptors (A 2A, D 2, CB 1, and mGlu 5, respectively) is revised under the “receptor mosaic” perspective. Furthermore, the concept of “hub receptor” is defined in accordance with informatics and it is tentatively illustrated in the case of the hypothesized tetramer formed by the above mentioned receptors. On the basis of some biochemical features of the four receptors and of a bioinformatics analysis, an objective deduction of their “similarity” has been obtained. To this aim the Canberra, Euclidean and Chebyshev multivariate distance metrics have been used. It is interesting to note that A 2A and D 2 are the most different ones, while CB 1 and mGlu 5 are the most similar ones among the four receptors analyzed. Finally, by means of a bioinformatics analysis based on different approaches the possible binding sites mediating G-protein-coupled receptor (GPCR) interactions have been indicated. It is interesting to note that in some instances accordance has been found between the bioinformatics indications and the available experimental data. 相似文献
16.
1. The serotonin 1A(5-HT 1A) receptors are members of a superfamily of seven transmembrane domain receptors that couple to G-proteins. They appear to be involved in various behavioral and cognitive functions. Although specific 5-HT 1Aagonists have been discovered more than a decade back, the development of selective 5-HT 1Aantagonists has been achieved only recently.2. We have examined the modulation of the specific antagonist [ 3H] p-MPPF binding to 5-HT 1Areceptors from bovine hippocampal membranes by monovalent and divalent metal ions. Our results show that the antagonist binding to 5-HT 1Areceptors is inhibited by both monovalent and divalent cations in a concentration-dependent manner. This is accompanied by a concomitant reduction in binding affinity.3. Our results also show that the specific antagonist p-MPPF binds to all available receptors in the bovine hippocampal membrane irrespective of their state of G-protein coupling and other serotonergic ligands such as 5-HT and OH-DPAT effectively compete with the specific antagonist [ 3H] p-MPPF.4. These results are relevant to ongoing analyses of the overall modulation of ligand binding in G-protein-coupled seven transmembrane domain receptors. 相似文献
17.
1. Serotonin is an intrinsically fluorescent biogenic amine that acts as a neurotransmitter and is found in a wide variety of sites in the central and peripheral nervous system. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions.2. Serotonin exerts its diverse actions by binding to distinct cell surface receptors which have been classified into many groups. The serotonin 1A (5-HT 1A) receptor is the most extensively studied of the serotonin receptors and belongs to the large family of seven transmembrane domain G-protein coupled receptors.3. The tissue and sub-cellular distribution, structural characteristics, signaling of the serotonin 1A receptor and its interaction with G-proteins are discussed.4. The pharmacology of serotonin 1A receptors is reviewed in terms of binding of agonists and antagonists and sensitivity of their binding to guanine nucleotides.5. Membrane biology of 5-HT 1A receptors is presented using the bovine hippocampal serotonin 1A receptor as a model system. The ligand binding activity and G-protein coupling of the receptor is modulated by membrane cholesterol thereby indicating the requirement of cholesterol in maintaining the receptor organization and function. This, along with the reported detergent resistance characteristics of the receptor, raises important questions on the role of membrane lipids and domains in the function of this receptor. 相似文献
18.
Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Like other class B G protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R) were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) peptide ligands indicates that the antagonist exendin-4 [9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4 [9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands. 相似文献
19.
Abstract: Previous studies have demonstrated species-specific differences in 5-hydroxytryptamine 3 (5-HT 3) receptors, but unequivocal evidence of 5-HT 3 receptor subtypes, within a species, has not yet been obtained. The purpose of the current study was to test for heterogeneity in 5-HT 3 receptors in murine tissues. 5-HT 3 receptors in membranes derived from brain cerebral cortex of CD-1, C57BI/6, and Swiss Webster mice and ileum of CD-1 mice were labeled with the 5-HT 3 receptor antagonist [ 3H]RS-42358–197. Structurally diverse competing ligands were then used to characterize the binding site. [ 3H]RS-42358-197 bound with similar affinity in each of the cortical tissues (mean KD= 0.14 n M; range, 0.06–0.32 n M) but bound with lower affinity in ileal tissue (2.5 n M). The density of sites labeled with [ 3H]RS-42358–197 ranged from 10.4 fmol/mg of protein in Swiss Webster mouse cortex to 44.2 fmol/mg of protein in Sprague-Dawley rat cortex. Displacing ligands produced a pharmacologic profile of the [ 3H]RS-42358–197 binding site consistent with it being a 5-HT 3 receptor: ( R)-YM060 > (S)-zacopride > (R)-zaco-pride > MDL 72222 > 2-methyl-5-HT. However, 10-fold differences in the affinity of certain ligands were found when comparing 5-HT 3 binding sites in membranes from cerebral cortex of the different strains of mice and when comparing 5-HT 3 binding sites in brain and ileal membranes prepared from the CD-1 mouse strain. Ligands demonstrating selectivity included RS-42358–197, ( R)-za-copride, 1-( m-chlorophenyl) biguanide, ( R)-YM060, and MDL 72222. These studies demonstrate tissue-and strain-dependent differences in murine 5-HT 3 binding sites. This suggests that 5-HT 3 receptors exist as multiple subtypes within species and that subtype-selective 5-HT 3 ligands may be identified. 相似文献
20.
The nucleotide receptors P2Y 2 and P2Y 4 are the most closely related G protein-coupled receptors (GPCRs) of the P2Y receptor (P2YR) family. Both subtypes couple to G q proteins and are activated by the pyrimidine nucleotide UTP, but only P2Y 2R is also activated by the purine nucleotide ATP. Agonists and antagonists of both receptor subtypes have potential as drugs e.g. for neurodegenerative and inflammatory diseases. So far, potent and selective, “drug-like” ligands for both receptors are scarce, but would be required for target validation and as lead structures for drug development. Structural information on the receptors is lacking since no X-ray structures or cryo-electron microscopy images are available. Thus, we performed receptor homology modeling and docking studies combined with mutagenesis experiments on both receptors to address the question how ligand binding selectivity for these closely related P2YR subtypes can be achieved. The orthosteric binding site of P2Y 2R appeared to be more spacious than that of P2Y 4R. Mutation of Y197 to alanine in P2Y 4R resulted in a gain of ATP sensitivity. Anthraquinone-derived antagonists are likely to bind to the orthosteric or an allosteric site depending on their substitution pattern and the nature of the orthosteric binding site of the respective P2YR subtype. These insights into the architecture of P2Y 2- and P2Y 4Rs and their interactions with structurally diverse agonists and antagonist provide a solid basis for the future design of potent and selective ligands. 相似文献
|