Abstract:
:Herein we propose the D-Trp-Phe sequence within an inverse type II β-turn as a new kind of pharmacophoric motif for μ-opioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-D-Pro-D-Trp-Phe-Gly] (4), an analogue of endomorphin-1 (H-Tyr-Pro-Trp-Phe-NH₂) lacking the crucial protonatable amino group of Tyr 1, is a MOR agonist with 10⁻⁸ M affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve D-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II β-turn. These efforts led to c[Tyr-Gly-D-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[D-Asp-1-amide-β-Ala-D-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the κ- and δ-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse β-turn in binding. These results indicate that the D-Trp-Phe inverse β-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Gentilucci L,Tolomelli A,De Marco R,Spampinato S,Bedini A,Artali Rdoi
10.1002/cmdc.201100169subject
Has Abstractpub_date
2011-09-05 00:00:00pages
1640-53issue
9eissn
1860-7179issn
1860-7187journal_volume
6pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::The metal ion chelating β-N-hydroxy-γ-ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold, leading to N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as hepatitis C virus (HCV) NS5B polymerase inhibitors. Lead optimization led to the identification of N-phenylpropyl c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200058
更新日期:2012-05-01 00:00:00
abstract::Polo-like kinase 1 (PLK1) plays crucial functions in multiple stages of mitosis and is considered to be a potential drug target for cancer therapy. The functions of PLK1 are mediated by its N-terminal kinase domain and C-terminal polo-box domain (PBD). Most inhibitors targeting the kinase domain of PLK1 have a selecti...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402284
更新日期:2015-01-01 00:00:00
abstract::Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario. Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120. However, due to a variety of reasons such as solubility...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200584
更新日期:2013-03-01 00:00:00
abstract::The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900478
更新日期:2019-11-20 00:00:00
abstract::ABC, it's easy as 1 2 3! Bioisosteric replacement of the anilide core by an indole moiety considerably increased stability and gave potent and selective ABCG2 (BCRP) inhibitors. Some compounds are superior to the reference substances fumitremorgin C and Ko143 in terms of potency and efficacy and are the most potent AB...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300319
更新日期:2013-11-01 00:00:00
abstract::PH-797804 ((aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100439
更新日期:2012-02-06 00:00:00
abstract::3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives were synthesized, and their structures were confirmed by single-crystal X-ray diffraction. This reaction yields the 1,4-dicarboxamide derivatives rather than the 1,2-dicarboxamide derivatives. Their in vitro antitumor activities were evaluated against SGC-79...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200109
更新日期:2012-06-01 00:00:00
abstract::Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including ge...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300259
更新日期:2014-03-01 00:00:00
abstract::The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily that affects immune response, development, and metabolism in target tissues. Glucocorticoids are widely used to treat diverse pathophysiological conditions, but their clinical applicability is limited by side effects. A prediction of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800274
更新日期:2009-01-01 00:00:00
abstract::The enzyme cyclooxygenase-2 (COX-2) is overexpressed in many cancers, cardiovascular disease, neurodegenerative disorders, and arthritis. Selective inhibitors of COX-2 have been developed as therapeutics or preventive agents for these diseases. However, recent reports have revealed a significant increase in cardiovasc...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200500032
更新日期:2006-06-01 00:00:00
abstract::A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000083
更新日期:2010-07-05 00:00:00
abstract::Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of thei...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800422
更新日期:2009-04-01 00:00:00
abstract::The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600125
更新日期:2006-10-01 00:00:00
abstract::Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and i...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000122
更新日期:2020-06-04 00:00:00
abstract::Opening up ion channels: We synthesised a series of anthraquinone analogues, called the GoSlo-SR family. Their effects on bladder smooth muscle BK channels were examined and, as shown, shifted voltage dependent activation >-100 mV (at 10 μM). They were more efficacious than NS11021 and could provide a new scaffold for...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200321
更新日期:2012-10-01 00:00:00
abstract::Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300166
更新日期:2013-08-01 00:00:00
abstract::First reported in the late 1930s and partly explained in 1970, the antibacterial activity of pectin remained almost ignored until the late 1990s. The concomitant emergence of research on natural antibacterials and new usages of pectin polysaccharides, including those in medicine widely researched in Russia, has led to...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000518
更新日期:2020-08-28 00:00:00
abstract::Herein we report the synthesis, photophysical properties, positron emission tomography (PET) imaging and photodynamic therapy (PDT) efficacy of methyl 3-(1'-m-iodobenzyloxy)ethyl-3-devinyl-verdin 4 (with or without the 124 I isotope). The PET imaging ability and ex vivo biodistribution of [124 I]4 were compared with t...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900352
更新日期:2019-08-20 00:00:00
abstract::Apelin is the endogenous ligand of the APJ receptor, a member of the G-protein-coupled receptor family. The apelin-APJ complex has been detected in many tissues and is emerging as a promising target for several pathophysiological conditions. There is currently little information on the structure-activity relationship ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100492
更新日期:2012-02-06 00:00:00
abstract::In an attempt to develop potent anticancer agents, a series of 2-anilinonicotinyl-linked acrylamide conjugates were designed, synthesized, and evaluated for cytotoxic activity against various human cancer cell lines, anti-tubulin activity and cell-cycle effects. Among the series, compounds 6 d [(E)-N-(6-fluorobenzo[d]...
journal_title:ChemMedChem
pub_type: 杂志文章,收录出版
doi:10.1002/cmdc.201400036
更新日期:2014-03-28 00:00:00
abstract::Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1-specific inhibitors have been pursued. Trans-2-ph...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000014
更新日期:2020-05-06 00:00:00
abstract::In an approach to design drugs with higher affinity for π-π stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2 (L)}2 -μ-{trans-1,4-dach}](NO3 )4 ((A)2 =(NH3 )2 or ethylenediamine (en), L=quinoline (quin) or benzothiazole (bztz), dach=trans-1,4-diaminocyclohexane) wer...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402052
更新日期:2014-06-01 00:00:00
abstract::Platinum amidine complexes represent a new class of potential antitumor drugs that contain the imino moiety HN=C(sp(2)) bonded to the platinum center. They can be related to the iminoether derivatives, which were recently shown to be the first Pt(II) compounds with a trans configuration endowed with anticancer activit...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201100150
更新日期:2011-07-04 00:00:00
abstract::Metalloproteinases of the astacin family are drawing ever increasing attention as potential drug targets. However, knowledge regarding inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is high selectivity, to avoid side effects brought about by inhibition of off-tar...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800300
更新日期:2018-08-20 00:00:00
abstract::Steroid derivatives bearing fluorescent groups such as anthracene, dansyl, deazaflavin, and pyrene attached to C6 were synthesized. These compounds are unique inhibitors of cytochrome P450 3A4 (CYP3A4) and display similar IC(50) values in the microM range for the CYP3A4 substrates midazolam, testosterone, and nifedipi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600300
更新日期:2007-05-01 00:00:00
abstract::In atomic force microscopy (AFM) a sharp cantilever tip is used to scan surfaces at the atomic level. One further application is force spectroscopy, in which force-distance curves between binding partners located on the cantilever and substrate surface are determined. This requires specifically immobilized molecules. ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402165
更新日期:2014-09-01 00:00:00
abstract::Over the years, a number of dimensionality reduction techniques have been proposed and used in chemoinformatics to perform nonlinear mappings. In this study, four representatives of nonlinear dimensionality reduction methods related to two different families were analyzed: distance-based approaches (Isomap and Diffusi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201400027
更新日期:2014-05-01 00:00:00
abstract::The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500507
更新日期:2016-06-20 00:00:00
abstract::The design and synthesis of heparin mimetics with high anticancer activity but no anticoagulant activity is an important task in medicinal chemistry. Here, we present the efficient synthesis of five Glc-GlcA-Glc sequenced and one Glc-IdoA-Glc sequenced non-glycosaminoglycan, heparin-related trisaccharides with various...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000917
更新日期:2021-01-12 00:00:00
abstract::Tau-tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that putatively phosphorylates residues including S422 in tau protein. Hyperphosphorylation of tau protein is the primary cause of tau pathology and neuronal death associated with Alzheimer's disease. A library of 12 truncation variants comprising the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300274
更新日期:2013-11-01 00:00:00