共查询到20条相似文献,搜索用时 0 毫秒
1.
Bignan GC Battista K Connolly PJ Orsini MJ Liu J Middleton SA Reitz AB 《Bioorganic & medicinal chemistry letters》2005,15(22):5022-5026
A novel series of indolin-2-ones having a spirocyclic piperidine ring at the 3-position was synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated. Substitution on the phenyl ring and nitrogen atom of the indolin-2-one core generated several selective high-affinity ligands that were antagonists of the ORL-1 receptor. 相似文献
2.
Faghih R Dwight W Vasudevan A Dinges J Conner SE Esbenshade TA Bennani YL Hancock AA 《Bioorganic & medicinal chemistry letters》2002,12(21):3077-3079
Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H(3) receptors. 相似文献
3.
McDevitt RE Malamas MS Manas ES Unwalla RJ Xu ZB Miller CP Harris HA 《Bioorganic & medicinal chemistry letters》2005,15(12):3137-3142
The syntheses of a series of 2-arylindene-1-ones as potent ligands of ERbeta and ERalpha are described. Several compounds exhibited high potency and moderate selectivity for the ERbeta receptor. X-ray and modeling studies were used to understand ligand binding orientation and observed affinity. 相似文献
4.
Conformationally-flexible benzamide analogues as dopamine D3 and sigma 2 receptor ligands 总被引:1,自引:0,他引:1
Mach RH Huang Y Freeman RA Wu L Vangveravong S Luedtke RR 《Bioorganic & medicinal chemistry letters》2004,14(1):195-202
A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine (D2, D3 and D4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (K(i) value=2nM) and moderate selectivity (30-fold) for D3 compared to D2 receptors. In addition, this series of compounds were also tested for affinity at sigma1 and sigma2 receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for sigma2 versus sigma1 receptors. Consequently, these novel compounds may be useful for characterizing the functional role of sigma2 receptors and for imaging the sigma2 receptor status of tumors in vivo with PET. 相似文献
5.
DD Dixon MA Tius GA Thakur H Zhou AL Bowman VG Shukla Y Peng A Makriyannis 《Bioorganic & medicinal chemistry letters》2012,22(16):5322-5325
A series of tricyclic cannabinoids incorporating a heteroaroyl group at C3 were prepared as probes to explore the binding site(s) of the CB1 and CB2 receptors. This relatively unexplored structural motif is shown to be CB2 selective with K(i) values at low nanomolar concentrations when the heteroaromatic group is 3-benzothiophenyl (41) or 3-indolyl (50). When photoactivated, the lead compound 41 was shown to successfully label the CB2 receptor through covalent attachment at the active site while 50 failed to label. The benzothiophenone moiety may be a photoactivatable moiety suitable for selective labeling. 相似文献
6.
Based on the most stable conformation of ZD6169, a series of N-arylated derivatives of oxazolidindione (2), morpholin-3-one (3-5), piperidin-2-one (6), and pyrrolidin-2-one (7-13) was synthesized and evaluated for potassium channel opening activity. In the in-vitro assays, N-(4-benzoylphenyl)-piperidin-2-on (6) and N-(4-benzoylphenyl)-3,3-dimethyl-pyrrolidin-2-one (9) demonstrated potent and selective relaxant activity at the bladder detrusor muscle [IC50, bladder)=7.4 and 6.7 microM, respectively; IC50 ratio (portal vein/bladder)=41 and 51, respectively]. 相似文献
7.
Shiau TP Turtle ED Francavilla C Alvarez NJ Zuck M Friedman L O'Mahony DJ Low E Anderson MB Najafi RR Jain RK 《Bioorganic & medicinal chemistry letters》2011,21(10):3025-3028
Antimicrobial resistance against many known therapeutics is on the rise. We examined derivatives of 3-chlorooxazolidin-2-one 1a (X = H) as antibacterial and antifungal agents. The key findings were that the activity and apparent in vitro cytotoxicity could be controlled by the substitution of charged solubilizers at the 4- and 5- positions. These changes both significantly increase the antifungal potency and decrease cytotoxicity. Particularly effective were trialkylammonium groups which led to 400- to 600-fold increases in the antifungal therapeutic index when compared to their unsubstituted counterparts. 相似文献
8.
Tran JA Tucci FC Arellano M Jiang W Chen CW Marinkovic D Fleck BA Wen J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2008,18(6):1931-1938
Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers. 相似文献
9.
10.
Lavey BJ Kozlowski JA Shankar BB Spitler JM Zhou G Yang DY Shu Y Wong MK Wong SC Shih NY Wu J McCombie SW Rizvi R Wolin RL Lunn CA 《Bioorganic & medicinal chemistry letters》2007,17(13):3760-3764
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified. 相似文献
11.
Worm K Zhou QJ Saeui CT Green RC Cassel JA Stabley GJ DeHaven RN Conway-James N LaBuda CJ Koblish M Little PJ Dolle RE 《Bioorganic & medicinal chemistry letters》2008,18(9):2830-2835
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB2 receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB2 receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects. 相似文献
12.
Ewa Szymaska Darryl S. Pickering Birgitte Nielsen Tommy N. Johansen 《Bioorganic & medicinal chemistry》2009,17(17):6390-6401
On the basis of X-ray structures of ionotropic glutamate receptor constructs in complex with amino acid-based AMPA and kainate receptor antagonists, a series of rigid as well as flexible biaromatic alanine derivatives carrying selected hydrogen bond acceptors and donors have been synthesized in order to investigate the structural determinants for receptor selectivity between AMPA and the GluR5 subtype of kainate receptors. Compounds selective for either GluR5 or AMPA receptors were identified. One particular substituent position appeared to be of special importance for control of ligand selectivity. Using molecular modeling the observed structure–activity relationships at AMPA and GluR5 receptors were deduced. 相似文献
13.
Fang J Akwabi-Ameyaw A Britton JE Katamreddy SR Navas F Miller AB Williams SP Gray DW Orband-Miller LA Shearin J Heyer D 《Bioorganic & medicinal chemistry letters》2008,18(18):5075-5077
A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar. 相似文献
14.
Clark RD Ray NC Blaney P Crackett PH Hurley C Williams K Dyke HJ Clark DE Lockey PM Devos R Wong M White A Belanoff JK 《Bioorganic & medicinal chemistry letters》2007,17(20):5704-5708
The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive. 相似文献
15.
Aslanian R Zhu X Vaccaro HA Shih NY Piwinski JJ Williams SM West RE 《Bioorganic & medicinal chemistry letters》2008,18(18):5032-5036
A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat. 相似文献
16.
Nitrosamines as nicotinic receptor ligands 总被引:1,自引:0,他引:1
Schuller HM 《Life sciences》2007,80(24-25):2274-2280
Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention. 相似文献
17.
Dukat M Ramunno A Banzi R Damaj MI Martin B Glennon RA 《Bioorganic & medicinal chemistry letters》2005,15(19):4308-4312
An examination of several 3-(2-aminoethyl)pyridine analogs suggests that they likely orient at alpha4beta2 nicotinic cholinergic receptors in a different fashion than their correspondingly substituted nicotine analogs. 相似文献
18.
Shankar BB Lavey BJ Zhou G Spitler JA Tong L Rizvi R Yang DY Wolin R Kozlowski JA Shih NY Wu J Hipkin RW Gonsiorek W Lunn CA 《Bioorganic & medicinal chemistry letters》2005,15(20):4417-4420
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1. 相似文献
19.
Chen W Wu H Hernandez RJ Mehta AK Ticku MK France CP Coop A 《Bioorganic & medicinal chemistry letters》2005,15(13):3201-3202
Gamma-hydroxybutyric acid (GHB) is a drug of abuse, a therapeutic, and purportedly a neurotransmitter with a complex mechanism of action in vivo due to direct actions at GABA(B) as well as GHB receptors and because of its metabolism to GABA. Herein, we describe 3-ethers of 3-hydroxyphenylacetic acid, which have relatively high affinity at GHB sites, no significant affinity at GABA receptors, and would not be expected to be rapidly metabolized to GABAergic ligands. The selectivity of these compounds (UMB108, UMB109, and UMB119) could prove to be useful for studying the biology of GHB receptors, free from GABAergic effects. 相似文献
20.
Nicola Micale Roberta Ettari Tanja Schirmeister Astrid Evers Christoph Gelhaus Matthias Leippe Maria Zappal Silvana Grasso 《Bioorganic & medicinal chemistry》2009,17(18):6505-6511
A series of 1-aryl-6,7-disubstituted-2H-isoquinolin-3-ones (2–10) was synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2, as well as against cultured P. falciparum strain FCBR parasites. All compounds displayed inhibitory activity against recombinant falcipain-2 and against in vitro cultured intraerythrocytic P. falciparum, with the exception of 9. The new compounds exhibited no selectivity against human cysteine proteases such as cathepsins B and L. The inhibitory activity of the synthesized compounds was also evaluated against another protozoal cysteine protease, namely rhodesain of Trypanosoma brucei rhodesiense. 相似文献