共查询到20条相似文献,搜索用时 15 毫秒
1.
Massip S Guillon J Bertarelli D Bosc JJ Léger JM Lacher S Bontemps C Dupont T Müller CE Jarry C 《Bioorganic & medicinal chemistry》2006,14(8):2697-2719
The development of potent and selective adenosine receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of adenosine receptor antagonists and have been widely developed in terms of affinity and selectivity for adenosine receptors. We recently developed new original pathways for the synthesis of xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and beta-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic xanthine derivatives 1-4 from 5, and their evaluation as adenosine A1, A2A and A3 receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the xanthine core, while its introduction in the 1-position of the xanthine moiety led to a large decrease in adenosine receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)xanthine (2n) was the most potent and selective A2A antagonist of the present series (Ki=44 nM, >200-fold selective vs A1). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylxanthine (3f) was identified as a potent (KiA1=21 nM) and highly selective (>350-fold vs A2A and A3 receptor) adenosine A1 receptor antagonist. 相似文献
2.
Cacciari B Bolcato C Spalluto G Klotz KN Bacilieri M Deflorian F Moro S 《Purinergic signalling》2007,3(3):183-193
In the last 5 years, many efforts have been conducted searching potent and selective human A(3) adenosine antagonists. In this field several different classes of compounds, possessing very good affinity (nM range) and with a broad range of selectivity, have been proposed. Recently, our group synthesized a new series of pyrazolo-triazolo-pyrimidines bearing different substitutions at the N(5) and N(8) positions, which have been described as highly potent and selective human A(3) adenosine receptor antagonists. The present review summarizes available data and provides an overview of the structure-activity relationships found for this class of human A(3) adenosine receptor antagonists. 相似文献
3.
van Oeveren A Pio BA Tegley CM Higuchi RI Wu M Jones TK Marschke KB Negro-Vilar A Zhi L 《Bioorganic & medicinal chemistry letters》2007,17(6):1523-1526
A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays. 相似文献
4.
Palin R Barn DR Clark JK Cottney JE Cowley PM Crockatt M Evans L Feilden H Goodwin RR Griekspoor F Grove SJ Houghton AK Jones PS Morphy RJ Smith AR Sundaram H Vrolijk D Weston MA Wishart G Wren P 《Bioorganic & medicinal chemistry letters》2005,15(3):589-593
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified. 相似文献
5.
Matasi JJ Caldwell JP Hao J Neustadt B Arik L Foster CJ Lachowicz J Tulshian DB 《Bioorganic & medicinal chemistry letters》2005,15(5):1333-1336
In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor. 相似文献
6.
Several analogs of caffeine have been investigated as antagonists at A2 adenosine receptors stimulatory to adenylate cyclase in membranes from rat pheochromocytoma PC12 cells and human platelets and at A1 adenosine receptors inhibitory to adenylate cyclase from rat fat cells. Among these analogs, 1-propargyl-3,7-dimethylxanthine was about 4- to 7-fold and 7-propyl-1,3-dimethylxanthine about 3- to 4-fold more potent than caffeine at A2 receptors of PC12 cells and platelets. At A1 receptors of fat cells, both compounds were about 2-fold less potent than caffeine. These caffeine analogs have an A1/A2 selectivity ratio of about 10-20 and are the first selective A2 receptor antagonists yet reported. The results may provide the basis for the further development of highly potent and highly selective A2 adenosine receptor antagonists. 相似文献
7.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-7):607-609
4′-Thionucleoside derivatives as potent and selective A3 adenosine receptor agonists were synthesized, starting from d-gulono-γ-lactone via d-thioribosyl acetate as a key intermediate, among which the 2-chloro-N6-methyladenosine-5′-methyluronamide showed the most potent and selective binding affinity (Ki=0.28±0.09 nM) at the human A3 adenosine receptor. 相似文献
8.
David J Rawson Kevin N Dack Roger P Dickinson Kim James 《Bioorganic & medicinal chemistry letters》2002,12(2):125-128
Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET(A) antagonists. The most potent antagonist, 32, (ET(A) IC(50)=0.55nM) is 722-fold selective over the ET(B) receptor, as measured by binding experiments. 相似文献
9.
Mizutani T Nagase T Ito S Miyamoto Y Tanaka T Takenaga N Tokita S Sato N 《Bioorganic & medicinal chemistry letters》2008,18(23):6041-6045
Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H(3) receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K(+) channel and human alpha(1A)-adrenoceptor activities is the main focus of the present study. 相似文献
10.
Studies of the physiological actions of melatonin have been hindered by the lack of specific, potent and subtype selective agonists and antagonists. In the present study, we describe the utility of a melanophore cell line from Xenopus laevis for exploring structure-activity relationships among novel melatonin analogues and report a novel MT2-selective agonist (IIK7) and MT2-selective receptor antagonist (K185). IIK7 is a potent melatonin receptor agonist in the melanophore model, and in NIH3T3 cells expressing human mt1 and MT2 receptor subtypes. In radioligand binding experiments IIK7 is 90-fold selective for the MT2 subtype. K185 is devoid of agonist activity, but acts as a competitive melatonin antagonist in melanophores. A low concentration (10(-9) M) antagonizes melatonin inhibition of forskolin stimulation of cyclic AMP in NIH3T3 cells expressing human MT2 receptors, but has no effect in cells expressing mt1 receptors. In binding assays, K185 is 140-fold selective for the MT2 subtype. 相似文献
11.
Tran JA Pontillo J Arellano M Fleck BA Tucci FC Marinkovic D Chen CW Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(14):3434-3438
A series of cyclohexylpiperazines was synthesized as potent and selective antagonists of the human MC4 receptor. Compound 14t displayed binding affinity (Ki) of 4.2 and 1100 nM at MC4R and MC3R, respectively. 相似文献
12.
Li YH Tseng PS Evans KA Jaworski JP Morrow DM Fries HE Wu CW Edwards RM Jin J 《Bioorganic & medicinal chemistry letters》2010,20(22):6744-6747
A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described. 相似文献
13.
Lim MH Kim HO Moon HR Lee SJ Chun MW Gao ZG Melman N Jacobson KA Kim JH Jeong LS 《Bioorganic & medicinal chemistry letters》2003,13(5):817-820
Several 3'-fluoro analogues, 1a, 1b, and 1c of selective and potent adenosine A(3) receptor agonist, Cl-IB-MECA were synthesized from D-xylose via highly regioselective opening of lyxo-epoxides, 8a and 8b with fluoride anion. Compared to the high binding affinity of Cl-IB-MECA to the A(3) adenosine receptor, the corresponding 3'-fluoro derivative showed remarkably decreased binding affinity, indicating that 3'-hydroxyl group acts as hydrogen bonding acceptor, not hydrogen bonding donor like fluorine atom in binding to the A(3) adenosine receptor. 相似文献
14.
Hu B Malamas M Ellingboe J Largis E Han S Mulvey R Tillett J 《Bioorganic & medicinal chemistry letters》2001,11(8):981-984
As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor. 相似文献
15.
Nian Zhou Wayne Zeller Michael Krohn Herb Anderson Jun Zhang Emmanuel Onua Alex S. Kiselyov Jose Ramirez Guðrún Halldorsdottir Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(1):123-126
A series of potent and selective EP3 receptor antagonists are described. Utilizing a pharmacophore model developed for the EP3 receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays. 相似文献
16.
Philip J. Skinner Peter J. Webb Carleton R Sage Huong T. Dang Cameron C. Pride Ruoping Chen Susan Y. Tamura Jeremy G. Richman Daniel T. Connolly Graeme Semple 《Bioorganic & medicinal chemistry letters》2009,19(15):4207-4209
A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a. 相似文献
17.
Chen C Jiang W Tran JA Tucci FC Fleck BA Markison S Wen J Madan A Hoare SR Foster AC Marinkovic D Chen CW Arellano M Saunders J 《Bioorganic & medicinal chemistry letters》2008,18(1):129-136
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats. 相似文献
18.
Macor JE Gurley D Lanthorn T Loch J Mack RA Mullen G Tran O Wright N Gordon JC 《Bioorganic & medicinal chemistry letters》2001,11(3):319-321
The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors. 相似文献
19.
Skinner PJ Cherrier MC Webb PJ Sage CR Dang HT Pride CC Chen R Tamura SY Richman JG Connolly DT Semple G 《Bioorganic & medicinal chemistry letters》2007,17(23):6619-6622
A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series. 相似文献
20.
Murugesan N Gu Z Stein PD Spergel S Bisaha S Liu EC Zhang R Webb ML Moreland S Barrish JC 《Bioorganic & medicinal chemistry letters》2002,12(4):517-520
A number of 4'-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET(A)) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K(i)=0.9 nM) and selective for the ET(A) receptor, approximately equivalent to 1. 相似文献