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1.
A 5-HT? receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT?A receptor yielded substantial information concerning the analogues as 5-HT? receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT? receptor agonist, as it does not possess a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT? receptors by binding to an allosteric site in the receptor complex. 相似文献
2.
The apelin receptor (APJ) is a class A G‐protein‐coupled receptor (GPCR) and is a putative target for the treatment of cardiovascular and metabolic diseases. Apelin‐13 (NH2‐QRPRLSHKGPMPF‐COOH) is a vasoactive peptide and one of the most potent endogenous inotropic agents identified to date. We report the design and discovery of a novel APJ antagonist. By using a bivalent ligand approach, we have designed compounds with two ′affinity′ motifs and a short series of linker groups with different conformational and non‐bonded interaction properties. One of these, cyclo(1–6)CRPRLC‐KH‐cyclo(9–14)CRPRLC is a competitive antagonist at APJ. Radioligand binding in CHO cells transfected with human APJ gave a Ki value of 82 nM , competition binding in human left ventricle gave a KD value of 3.2 μM , and cAMP accumulation assays in CHO‐K1‐APJ cells gave a KD value of 1.32 μM . 相似文献
3.
Shagufta Dr. Dong Guo Elisabeth Klaasse Dr. Henk de Vries Johannes Brussee Dr. Lukáš Nalos Martin B. Rook Dr. Marc A. Vos Prof. Marcel A. G. van der Heyden Dr. Adriaan P. IJzerman Prof. 《ChemMedChem》2009,4(10):1722-1732
In this study we followed a new approach to analyze molecular substructures required for hERG channel blockade. We designed and synthesized 40 analogues of dofetilide ( 1 ), a potent hERG potassium channel blocker, and established structure–activity relationships (SAR) for their interaction with this important cardiotoxicity‐related off‐target. Structural modifications to dofetilide were made by diversifying the substituents on the phenyl rings and the protonated nitrogen and by varying the carbon chain length. The analogues were evaluated in a radioligand binding assay and SAR data were derived with the aim to specify structural features that give rise to hERG toxicity. 相似文献
4.
Structure-function analysis of a conserved aromatic cluster in the N- terminal domain of human epidermal growth factor 总被引:1,自引:0,他引:1
Murray MB; Tadaki DK; Campion SR; Lamerdin JA; Serpersu EH; Bradrick TD; Niyogi SK 《Protein engineering, design & selection : PEDS》1998,11(11):1041-1050
The importance of a cluster of conserved aromatic residues of human
epidermal growth factor (hEGF) to the receptor binding epitope is suggested
by the interaction of His10 and Tyr13 of the A-loop with Tyr22 and Tyr29 of
the N-terminal beta-sheet to form a hydrophobic surface on the hEGF
protein. Indeed, Tyr13 has previously been shown to contribute a
hydrophobic determinant to receptor binding. The roles of His10, Tyr22 and
Tyr29 were investigated by structure-function analysis of hEGF mutant
analogues containing individual replacements of each residue. Substitutions
with aromatic residues or a leucine at position 10 retained receptor
affinities and agonist activities similar to wild- type indicating that an
aromatic residue is not essential. Variants with polar, charged or
aliphatic substitutions altered in size and/or hydrophobicity exhibited
reduced binding and agonist activities. 1- Dimensional 1H NMR spectra of
high, moderate and low-affinity analogues at position 10 suggested only
minor alterations in hEGF native structure. In contrast, a variety of
replacements were tolerated at position 22 or 29 indicating that neither
aromaticity nor hydrophobicity of Tyr22 and Tyr29 is required for receptor
binding. CD spectra of mutant analogues at position 22 or 29 indicated a
correlation between loss of receptor affinity and alterations in hEGF
structure. The results indicate that similar to Tyr13, His10 of hEGF
contributes hydrophobicity to the receptor binding epitope, whereas Tyr22
and Tyr29 do not appear to be directly involved in receptor interactions.
The latter conclusion, together with previous studies, suggests that
hydrophobic residues on only one face of the N-terminal beta-sheet of hEGF
are important in receptor recognition.
相似文献
5.
Joanna Mataliska Katarzyna Kosiska Pawe K. Halik Przemysaw Ko
miski Piotr F. J. Lipiski Ewa Gniazdowska Aleksandra Misicka 《International journal of molecular sciences》2022,23(3)
Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with 68Ga and 177Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The 177Lu-radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the 177Lu-labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R-targeting vectors. 相似文献
6.
Carline Chaves-Almagro Johanna Auriau Alize Dortignac Pascal Clerc Hubert Lulka Simon Deleruyelle Fabrice Projetti Jessica Nakhl Audrey Frances Judit Berta Vronique Gigoux Daniel Fourmy Marlne Dufresne Anne Gomez-Brouchet Julie Guillermet-Guibert Pierre Cordelier Bernard Knibiehler Ralf Jockers Philippe Valet Yves Audigier Bernard Masri 《International journal of molecular sciences》2022,23(18)
Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease. 相似文献
7.
Dr. Dimitra T. Pournara Anna Durner Dr. Eftichia Kritsi Alexios Papakostas Dr. Panagiotis Zoumpoulakis Prof. Dr. Annette Nicke Dr. Maria Koufaki 《ChemMedChem》2020,15(24):2530-2543
The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide ( 56 ) exhibiting the best potency with an IC50 value of 0.39 μM. 相似文献
8.
Radi M Pagano M Franchi L Castagnolo D Schenone S Casaluce G Zamperini C Dreassi E Maga G Samuele A Gonzalo E Clotet B Esté JA Botta M 《ChemMedChem》2012,7(5):883-896
Previous studies aimed at exploring the SAR of C2-functionalized S-DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild-type RT and drug-resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild-type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compound suffers from a suboptimal ADME profile typical of many S-DABO analogues, but it could, however, represent a promising candidate as an anti-HIV microbicide. In the present work, a new series of S-DABO/N-DABO derivatives were synthesized to obtain additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. In vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration. 相似文献
9.
Development of Potent and Metabolically Stable APJ Ligands with High Therapeutic Potential
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Dr. Cathleen Juhl Dr. Sylvia Els‐Heindl Ria Schönauer Dr. Gorden Redlich Dr. Erik Haaf Dr. Frank Wunder Prof. Dr. Bernd Riedl Dr. Nils Burkhardt Prof. Dr. Annette G. Beck‐Sickinger Dr. Donald Bierer 《ChemMedChem》2016,11(21):2378-2384
The apelin ligand receptor system is an important target to develop treatment strategies for cardiovascular diseases. Although apelin exhibits strong inotropic effects, its pharmaceutical application is limited because no agonist with suitable properties is available. On the one hand, peptide ligands are too instable, and on the other hand, small‐molecule agonists show only low potency. This study describes the development of apelin (APJ) receptor agonists with not only high activity but also metabolic stability. Several strategies including capping of termini, insertion of unnatural amino acids, cyclization, and lipidation were analyzed. Peptide activity was tested using a Ca2+‐mobilization assay and the degradation of selected analogues was analyzed in rat plasma. The best results were obtained by N‐terminal lipidation of a 13‐mer apelin derivative. This analogue displayed a half‐life of 29 h in rat plasma, compared with 0.025 h for the wild‐type peptide. Furthermore, in vivo pharmacokinetics revealed a clearance of 0.049 L h?1 kg?1 and a half‐life of 0.36 h. In summary, amino acid substitution and fatty acid modification resulted in a potent and 1000‐fold more stable peptide that exhibits high pharmaceutical potential. 相似文献
10.
Dr. Jianmei Cui Dr. Jinshan Jin Dr. Ying‐Hsin Hsieh Dr. Hsiuchin Yang Dr. Bowen Ke Dr. Krishna Damera Dr. Phang C. Tai Dr. Binghe Wang 《ChemMedChem》2013,8(8):1384-1393
SecA, a key component of bacterial Sec‐dependent secretion pathway, is an attractive target for exploring novel antimicrobials. Rose bengal (RB), a polyhalogenated fluorescein derivative, was found from our previous study as a potent SecA inhibitor. Here we describe the synthesis and structure–activity relationships (SAR) of 23 RB analogues that were designed by systematical dissection of RB. Evaluation of these analogues allowed us to establish an initial SAR in SecA inhibition. The antimicrobial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis. 相似文献
11.
Max von Delius Christine M. Le Bernhard Ellinger Maria Kuzikov Sheraz Gul Vy M. Dong 《Israel journal of chemistry》2017,57(10-11):975-981
Cytosporone B and its simple analogues (e. g., amoitone B) were recently identified as unique agonists for nuclear orphan receptor Nur77. In this study, we have developed an aldehyde C-H activation method for preparing natural and designer analogues from the cytosporone family. In addition, a comprehensive investigation of the compounds’ biological activities and pharmacological liabilities has been conducted and new structure activity relationships (SAR) were derived from the data. Most notably, we found that increased cytotoxicity can be obtained by virtue of fluorine substitution on the hydrophobic acyl chain. 相似文献
12.
Villard R Hammache D Delapierre G Fotiadu F Buono G Fantini J 《Chembiochem : a European journal of chemical biology》2002,3(6):517-525
Galactosylceramide (GalCer) is a glycosphingolipid (GSL) receptor that allows HIV-1 infection of CD4-negative cells from neural and intestinal tissues. A water-soluble analogue of GalCer that features its polar head and the characteristic galactose-ceramide linkage but lacks the carbohydrate chains was prepared as a single enantiomer from (S)-serine. This analogue was not recognized in binding tests with the HIV-1 surface envelope glycoprotein gp120 in solution, which revealed the crucial importance of the ceramide alkyl chains. Two series of water-soluble GalCer analogues that contained either a hexanoic or a decanoic acyl unit and a saturated nine-carbon sphingosine moiety were designed by using molecular modeling results from natural GSLs and analogues with truncated alkyl chains. The longer chain compounds exhibit the characteristic fundamental conformation of GalCer. Seven analogues were prepared from Garner's aldehyde according to a straightforward and efficient asymmetric synthesis. All of these compounds proved to be water soluble but did not bind to gp120 in a solid-phase binding assay. These analogues were thus tested by using surface pressure measurements on a monomolecular film of GalCer, which served as a model of the plasma membrane. The incorporation of analogues very similar to GalCer into a GalCer monolayer prevented the insertion of gp120, whereas a structurally different derivative was not active. Based on these data, the molecular bases for recognition of GSLs by gp120 were elucidated. The essential importance of the GSL conformation in the primary interaction event and the crucial role of the alkyl chains of the ceramide moiety in the secondary interactions and the insertion process were clearly established. 相似文献
13.
Monga V Meena CL Rajput S Pawar C Sharma SS Lu X Gershengorn MC Jain R 《ChemMedChem》2011,6(3):531-543
As part of our search for selective and CNS‐active thyrotropin‐releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH‐R1 and TRH‐R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH‐R1 and TRH‐R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R=CH3) exhibited binding affinities (Ki values) of 0.17 μM for TRH‐R1 and 0.016 μM for TRH‐R2; it is 10‐fold less potent than TRH in binding to TRH‐R1 and equipotent with TRH in binding to TRH‐R2. Compound 21 a , the most selective agonist, activated TRH‐R2 with a potency (EC50 value) of 0.0021 μM , but activated TRH‐R1 at EC50=0.05 μM , and exhibited 24‐fold selectivity for TRH‐R2 over TRH‐R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate‐induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a , b and 22 a , b decreased sleeping time by nearly 50 % more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ‐induced seizures, but failed to provide any protection in MES‐induced seizures at 10 μmol kg?1. The results of this study provide evidence that TRH analogues that show selectivity for TRH‐R2 over TRH‐R1 possess potent CNS activity. 相似文献
14.
Lennart Bunch Prof. Darryl S. Pickering Prof. Thierry Gefflaut Prof. Virginie Vinatier Dr. Virgil Helaine Ahmad Amir Birgitte Nielsen Anders A. Jensen Prof. 《ChemMedChem》2009,4(11):1925-1929
Subtype‐selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4‐substituted (S)‐glutamate (Glu) analogues were synthesized, and altogether this approach has provided important insight into the structure–activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4‐disubstituted Glu analogues 1 – 3 , which are hybrid structures of important 4‐substituted Glu analogues 4 – 8 , were investigated at iGluRs and EAATs. Collectively, their pharmacological profiles add new and valuable information to the SAR for the iGluRs and EAAT1–3. 相似文献
15.
Synthesis,Structure–Activity,and Structure–Stability Relationships of 2‐Substituted‐N‐(4‐oxo‐3‐oxetanyl) N‐Acylethanolamine Acid Amidase (NAAA) Inhibitors
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Romina Vitale Dr. Giuliana Ottonello Rita Petracca Sine Mandrup Bertozzi Dr. Stefano Ponzano Dr. Andrea Armirotti Dr. Anna Berteotti Dr. Mauro Dionisi Prof. Andrea Cavalli Prof. Daniele Piomelli Dr. Tiziano Bandiera Dr. Fabio Bertozzi 《ChemMedChem》2014,9(2):323-336
N‐Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator‐activated receptor‐α (PPAR‐α). Compounds that feature an α‐amino‐β‐lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti‐inflammatory effects that are mediated through FAE‐dependent activation of PPAR‐α. We synthesized and tested a series of racemic, diastereomerically pure β‐substituted α‐amino‐β‐lactones, as either carbamate or amide derivatives, investigating the structure–activity and structure–stability relationships (SAR and SSR) following changes in β‐substituent size, relative stereochemistry at the α‐ and β‐positions, and α‐amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β‐position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. 相似文献
16.
Spadoni G Bedini A Diamantini G Tarzia G Rivara S Lorenzi S Lodola A Mor M Lucini V Pannacci M Caronno A Fraschini F 《ChemMedChem》2007,2(12):1741-1749
Racemic N-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)acetamide (compound 5) was previously identified as a novel selective MT(2) antagonist fulfilling the requirements of pharmacophore and 3D QSAR models. In this study the enantiomers of 5 were separated by medium-pressure liquid chromatography and behaved as the racemate. Compound 5 was modified at the acylaminomethyl side chain and at position C8. The resulting analogues generally behaved as melatonin receptor antagonists (GTPgammaS test) with a modest degree of selectivity (up to 10-fold) for the MT(2) receptor. Changes at the amide side chain led to a decrease in binding affinity, whereas 8-acetyl and 8-methyl derivatives 12 and 11, respectively, were as potent as the 8-methoxy parent compound 5. Docking experiments with an MT(2) receptor model suggested binding modes consistent with the observed SARs and with the lack of selectivity of the enantiomers of 5. 相似文献
17.
18.
Korbinian Krieger Prof. Dr. Björn Wängler Prof. Dr. Ralf Schirrmacher Prof. Dr. Carmen Wängler 《ChemMedChem》2020,15(17):1652-1660
NPY(Y1)R (neuropeptide Y receptor subtype 1) is an important target structure for tumor-specific imaging and therapy as this receptor subtype is overexpressed in very high density and incidence especially in human breast cancer. Targeting this receptor with radiolabeled truncated analogues of the endogenous ligand NPY (neuropeptide Y) has, however, not yet resulted in satisfactory imaging results when using positron emission tomography (PET). This can be attributed to the limited stability of these PET imaging agents caused by their fast proteolytic degradation. Although highly promising NPY analogues were developed, their stability has only been investigated in very few cases. In this systematical work, we comparatively determined the stability of the five most promising truncated analogues of NPY that were developed over the last years, showing the highest receptor affinities and subtype selectivities. The stability of the peptides was assessed in human serum as well as in a human liver microsomal stability assay; these gave complementary results, thus demonstrating the necessity to perform both assays and not just conventional serum stability testing. Of the tested peptides, only [Lys(lauroyl)27,Pro30,Lys(DOTA)31,Bip32,Leu34]NPY27-36 showed high stability against peptidase degradation; thus this is the best-suited truncated NPY analogue for the development of NPY(Y1)R-specific imaging agents. 相似文献
19.
Benzocyclobutane,Benzocycloheptane and Heptene Derivatives as Melatonin Agonists and Antagonists
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Prof. Andrew Tsotinis Dr. Pandelis A. Afroudakis Prof. Peter J. Garratt Alina Bocianowska‐Zbrog Dr. David Sugden 《ChemMedChem》2014,9(10):2238-2243
Two series of analogues were designed, synthesised and evaluated as potential human melatonin type 1 and 2 receptor (hMT1 and hMT2) ligands. Their biological effects were assessed by a well‐established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the “melatonin” orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non‐melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT1 and MT2. These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4‐membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position. 相似文献
20.
Tacke R Popp F Müller B Theis B Burschka C Hamacher A Kassack MU Schepmann D Wünsch B Jurva U Wellner E 《ChemMedChem》2008,3(1):152-164
Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different. 相似文献