Abstract:
:The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N-(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT1/MT2 agonists and MT2-selective antagonists. We synthesized a new series of N-(anilinoalkyl)amides bearing 3-arylalkyloxy or 3-alkyloxy substituents at the aniline ring, looking for new potent and MT1-selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a, which was endowed with high MT1 binding affinity (pKi=8.93) and 78-fold selectivity for the MT1 receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3-arylalkyloxy substituent, we built a homology model of the MT1 receptor based on the β2 adrenergic receptor crystal structure in its activated state. A binding mode for MT1 agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT1 selectivity of compounds with lipophilic arylalkyloxy substituents.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Rivara S,Pala D,Lodola A,Mor M,Lucini V,Dugnani S,Scaglione F,Bedini A,Lucarini S,Tarzia G,Spadoni Gdoi
10.1002/cmdc.201200303subject
Has Abstractpub_date
2012-11-01 00:00:00pages
1954-64issue
11eissn
1860-7179issn
1860-7187journal_volume
7pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::Designed multitarget ligands are a popular approach to generating efficient and safe drugs, and fragment-based strategies have been postulated as a versatile avenue to discover multitarget ligand leads. To systematically probe the potential of fragment-based multiple ligand discovery, we have employed a large fragment...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000858
更新日期:2020-12-06 00:00:00
abstract::From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and n...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200403
更新日期:2013-02-01 00:00:00
abstract::Three photoswitchable tetrapeptides, based on a known synthetic antibacterial, were designed and synthesized to determine activity against Staphylococcus aureus. Each peptide contains an azobenzene photoswitch incorporated into either the N-terminal side chain (1), C-terminal side chain (2), or the C-terminus (3) to a...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000280
更新日期:2020-08-19 00:00:00
abstract::A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that 12 of the target compounds generally show better activity (MIC: <0.008-0.5 μg mL(-1)) agains...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200210
更新日期:2012-07-01 00:00:00
abstract::Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmod...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000653
更新日期:2020-11-24 00:00:00
abstract::A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC50 values in the mic...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900277
更新日期:2019-07-17 00:00:00
abstract::A series of new substituted 7-phenyl-3H-pyrrolo[3,2-f]quinolin-9-ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI(50) values in the nanomolar range. The active com...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000180
更新日期:2010-08-02 00:00:00
abstract::N-Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti-inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator-activated receptor α (PPAR-α). Thus, p...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300546
更新日期:2014-07-01 00:00:00
abstract::Half-sandwich rhodium(III) polypyridyl (pp) complexes with the metal atom capped by the facial crown thiaether 1,4,7-trithiacyclononane [9]aneS(3) represent a promising class of apoptosis-inducing potent cytostatic agents. The necrotic damage caused by the complexes is negligible. In vitro cytotoxicity assays with the...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000129
更新日期:2010-07-05 00:00:00
abstract::The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200377
更新日期:2013-01-01 00:00:00
abstract::In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300297
更新日期:2014-03-01 00:00:00
abstract::Despite various inhibitors targeting the zinc center(s) of enzymes, drugs that target zinc fingers have not been examined in detail. We previously developed a dithiol compound named SN-1 that has an inhibitory effect on the function of zinc finger transcription factors, but its mechanism of action has not yet been elu...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700399
更新日期:2017-12-07 00:00:00
abstract::The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last-reso...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700788
更新日期:2018-04-06 00:00:00
abstract::Computational chemistry has shown that backbone-alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene-to-metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine-step synthetic pathway we devised to...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500234
更新日期:2015-09-01 00:00:00
abstract::Many methods have been developed to capture the biological similarity between two compounds for use in drug discovery. A variety of similarity metrics have been introduced, the Tanimoto coefficient being the most prominent. Many of the approaches assume that molecular features or descriptors that do not relate to the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800290
更新日期:2009-02-01 00:00:00
abstract::The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X-ray structure of the c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600242
更新日期:2007-06-01 00:00:00
abstract::Phospholipid bilayers represent a complex, anisotropic environment fundamentally different from bulk oil or octanol, for instance. Even "simple" drug association to phospholipid bilayers can only be fully understood if the slab-of-hydrocarbon approach is abandoned and the complex, anisotropic properties of lipid bilay...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200900052
更新日期:2009-08-01 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::Targeted structural modifications have led to a novel type of buprenorphine-derived opioid receptor ligand displaying an improved selectivity profile for the μ-OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, witho...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000180
更新日期:2020-07-03 00:00:00
abstract::The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recen...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402278
更新日期:2014-12-01 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::Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700824
更新日期:2018-04-23 00:00:00
abstract::Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700730
更新日期:2018-04-06 00:00:00
abstract::The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700731
更新日期:2018-02-20 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::The ferrocenyl diphenol complexes 1,1-bis(4'-hydroxyphenyl)-2-ferrocenyl-but-1-ene (1) and 1,2-bis(4'-hydroxyphenyl)-1-ferrocenyl-but-1-ene [(Z)-2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1 is far more cytotox...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900430
更新日期:2019-10-04 00:00:00
abstract::Having oxaliplatin as archetype, several platinum complexes with a carbohydrate moiety resembling the cyclohexane-1,2-diamine ligand of oxaliplatin have been prepared. As leaving groups, the anionic ligands iodide, oxalate, and malonate were utilized, and for comparison purposes the chloro complex was employed. All co...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600279
更新日期:2007-04-01 00:00:00
abstract::The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly in...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000456
更新日期:2011-03-07 00:00:00
abstract::A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyrimidin-4(3H)-ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti-HIV activity in MT-4 cells. Most of these new congeners exhibited moderate to good activities against the wild-...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000555
更新日期:2011-05-02 00:00:00
abstract::Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900459
更新日期:2010-03-01 00:00:00