共查询到20条相似文献,搜索用时 15 毫秒
1.
Nicolas Moitessier Hervé Minoux Bernard Maigret Françoise Chrétien Yves Chapleu 《International journal of peptide research and therapeutics》1998,5(2-3):75-78
Summary Modeling studies of several known antagonists of the fibrinogen receptor have provided a theoretical pattern of the essential
characteristics for high affinity and selectivity toward this receptor. Potentially active and selective antagonists of the
fibrinogen receptor were thus designed by computational comparison of their aqueous conformations with that of known selective
antagonists, and synthesized by grafting suitable functional groups on a D-xylose scaffold. 相似文献
2.
Hervé Minoux Nicolas Moitessier Yves Chapleur Bernard Maigret 《International journal of peptide research and therapeutics》1997,4(4-6):463-466
Summary The aim of this work was to elucidate, using molecular modeling, structural and electrostatic common parameters of several
selective fibrinogen receptor antagonists. From this theoretical pattern, we are currently designing and synthesizing original
non-peptidic and selective carbohydrate-based antagonists of the fibrinogen receptor. 相似文献
3.
Hervé Minoux Nicolas Moitessier Yves Chapleur Bernard Maigret 《Letters in Peptide Science》1997,4(4-6):463-466
The aim of this work was to elucidate, usingmolecular modeling, structural and electrostaticcommon parameters of several selective fibrinogenreceptor antagonists. From this theoretical pattern,we are currently designing and synthesizing originalnon-peptidic and selective carbohydrate-basedantagonists of the fibrinogen receptor. 相似文献
4.
Dowling JE Vessels JT Haque S Chang HX van Vloten K Kumaravel G Engber T Jin X Phadke D Wang J Ayyub E Petter RC 《Bioorganic & medicinal chemistry letters》2005,15(21):4809-4813
Potent and selective antagonists of the adenosine A2A receptor often contain a nitrogen-rich fused-ring heterocyclic core. Replacement of the core with an isomeric ring system has previously been shown to improve target affinity, selectivity, and in vivo activity. This paper describes the preparation, by a novel route, of A2A receptor antagonists containing the [1,2,4]triazolo[1,5-a]pyrazine nucleus, which is isomeric with the [1,2,4]triazolo[1,5-c]pyrimidine core of a series of known A2A antagonists with in vivo activity in animal models of Parkinson's disease. 相似文献
5.
Janez Ilas Ferenc Hudecz Helga Süli-Vargha Danijel Kikelj 《Journal of peptide science》2008,14(8):946-953
Peptide leads D-Phe-Pro-Arg for thrombin inhibition and Arg-Gly-Asp for antagonistic activity on fibrinogen receptor were combined in one molecule in order to produce compounds capable of acting both as thrombin inhibitors and as fibrinogen receptor antagonists. Peptide conjugate 7 possessing both leads joined by a tetraglycine linker as well as tripeptides and peptidomimetics with highly overlapped D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups were prepared. Conjugate 7 was found to possess antagonistic activity on fibrinogen receptor, but was unexpectedly inactive as thrombin inhibitor. Compound 9 comprising of highly integrated D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups was found to possess a moderate but well balanced thrombin inhibitory and fibrinogen receptor antagonistic activity. Copyright (c) 2008 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
6.
Patane MA DiPardo RM Newton RC Price RP Broten TP Chang RS Ransom RW Di Salvo J Nagarathnam D Forray C Gluchowski C Bock MG 《Bioorganic & medicinal chemistry letters》2000,10(15):1621-1624
A novel class of potent and selective alpha-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known alpha-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described. 相似文献
7.
Webb TR Melman N Lvovskiy D Ji XD Jacobson KA 《Bioorganic & medicinal chemistry letters》2000,10(1):31-34
Pharmacophore queries from previously known potent selective A3 antagonists were generated by Chem-X. These queries were used to search a pharmacophore database of diverse compounds (CNS-Set). In vitro assays of 186 'hits' yielded over 30 active compounds, for four adenosine receptor subtypes. This search strategy may also be applicable to the discovery of new ligands via receptor homology data. 相似文献
8.
Sardar VM Bautista DL Fischer DJ Yokoyama K Nusser N Virag T Wang DA Baker DL Tigyi G Parrill AL 《Biochimica et biophysica acta》2002,1582(1-3):309-317
Recent characterization of lysophosphatidic acid (LPA) receptors has made possible studies elucidating the structure-activity relationships (SAR) for agonist activity at individual receptors. Additionally, the availability of these receptors has allowed the identification of antagonists of LPA-induced effects. Two receptor-subtype selective LPA receptor antagonists, one selective for the LPA1/EDG2 receptor (a benzyl-4-oxybenzyl N-acyl ethanolamide phosphate, NAEPA, derivative) and the other selective for the LPA3/EDG7 receptor (diacylglycerol pyrophosphate, DGPP, 8:0), have recently been reported. The receptor SAR for both agonists and antagonists are reviewed, and the molecular basis for the difference between agonism and antagonism as well as for receptor-subtype antagonist selectivity identified by molecular modeling is described. The implications of the newly available receptor-subtype selective antagonists are also discussed. 相似文献
9.
《Life sciences》1995,56(15):PL285-PL290
The mechanism of the antinociceptive effect of buprenorphine was assessed by administering selective μ-, μ1-, δ- and κ-opioid receptor antagonists in mice. Intraperitoneal administration of buprenorphine, at doses of 0.3 to 3 mg/kg, produced dose-dependent antinociception in the tail-flick test. The antinociceptive activity of buprenorphine did not result from the activation of κ- or δ-opioid receptors, since treatment with either nor-binaltorphimine, a selective κ-opioid receptor antagonist, or naltrindole, a selective δ-opioid receptor antagonist, was completely ineffective in blocking buprenorphine-induced antinociception. However, the antinociceptive effect of buprenorphine was significantly antagonized by β-funaltrexamine, a selective μ-opioid receptor antagonist. Moreover, selective μ1-opioid receptor antagonists, naloxonazine and naltrexonazine, also significantly antagonized the antinociceptive effect of buprenorphine. Co-administration of κ- and δ-opioid receptor antagonists with the μ-opioid receptor antagonists had no significant effect on the antagonistic profiles of the μ-opioid receptor antagonists on the antinociceptive effect of buprenorphine. These results suggest that buprenorphine acts selectively at μ1-opioid receptors to induce antinociceptive effects in mice. 相似文献
10.
Wilkinson JM Hayes S Thompson D Whitney P Bi K 《Journal of biomolecular screening》2008,13(8):755-765
A major focus in the current discovery of drugs targeting nuclear receptors (NRs) is identifying drugs with reduced side effects by improving selectivity, not only from other receptors but also by selective modulation of the NR of interest. Cellular assays not only provide valuable information on functional activity, potency, and selectivity but also are ideally suited for differentiating partial agonists and antagonists. The ability to partially activate a receptor is believed to be closely tied to the ability to selectively modulate the NR, resulting in expression of a subset of the normally regulated genes. To this end, the authors have built a complete panel of cell-based steroid hormone receptor assays for the androgen receptor, estrogen receptor alpha, estrogen receptor beta, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor by stably engineering a Gal4 DNA-binding domain/nuclear receptor ligand-binding domain fusion protein into an upstream activation sequence beta-lactamase reporter cell line. Each assay was validated with known agonists and antagonists for correct pharmacology and high-throughput compatibility. To demonstrate the utility of these assays, the authors profiled 35 pharmacologically relevant compounds in a dose-response format against the panel in both agonist and antagonist modes. The results demonstrated that selective estrogen receptor modulators can be identified and differentiated, as well as mixed and partial agonists and antagonists easily detected in the appropriate assays. Importantly, a comparison of the chimeric assays with full-length reporter gene assay data from the literature shows a good degree of correlation in terms of selectivity and pharmacology of important ligands. Taken together, these steroid hormone receptor assays provide good selectivity, sensitivity, and appropriate pharmacology for high-throughput screening and selectivity profiling of modulators of steroid hormone receptors. 相似文献
11.
The dopamine receptor antagonists SCH 23390 and spiperone show highly selective in vitro affinity for D-1 and D-2 dopamine receptor subtypes, respectively. We studied the effects of these selective antagonists on the supersensitive locomotor response to apomorphine in rats following 6- hydroxydopamine (6OHDA) lesions of the nucleus accumbens (N. Acc.). Both D-1 and D-2 receptor antagonists produced dose-dependent blockade of the supersensitive locomotor response at doses that did not depress baseline locomotor activity. The behavioral properties of these D-1 and D-2 receptor antagonists were further examined using a simple step-down motor task. Both antagonists produced catalepsy as evidenced by dose-dependent increases in step- down latency. These results indicate that drugs with distinct in vitro dopamine binding affinities cannot be distinguished on the basis of their ability to inhibit supersensitive locomotor activity or simple motor tasks in rats in vivo. 相似文献
12.
The solution structures and inter-molecular interaction of the cyclic melanocortin antagonists SHU9119, JKC363, HS014, and
HS024 with receptor molecules have been determined by NMR spectroscopy and molecular modeling. While SHU9119 is known as a
nonselective antagonist, JKC363, HS014, and HS024 are selective for the melanocortin subtype-4 receptor (MC4R) involved in
modulation of food intake. Data from NMR and molecular dynamics suggest that the conformation of the Trp9 sidechain in the
three MC4R-selective antagonists is quite different from that of SHU9119. This result strongly supports the concept that the
spatial orientation of the hydrophobic aromatic residue is more important for determining selectivity than the presence of
a basic, “arginine-like” moiety responsible for biological activity. We propose that the conformation of hydrophobic residues
of MCR antagonists is critical for receptor-specific selectivity. 相似文献
13.
We investigated the effect of melanocortin 4 receptor (MC4) antagonists on food intake in mice. Food intake during the light phase was significantly increased by ICV administration of mixed MC3/MC4 antagonists (AgRP and SHU9119) or MC4 selective antagonist peptide [(Cyclo (1-5)[Suc-D-Nal-Arg-Trp-Lys]NH2] (MBP10) and the small molecule antagonists THP and NBI-30. Both mixed and selective antagonists significantly reversed anorexia induced by ICV administration of the MC4 agonist (c (1-6) HfRWK-NH2) and the cytokine IL-1beta. These findings provide pharmacological evidence that the MC4 receptor mediates the effects of melanocortin agonists and antagonists on food intake in mice, and support the idea that selective small molecule MC4 antagonists may be useful as therapeutics for cachexia. 相似文献
14.
Swati P. Mercer Anthony J. Roecker Susan Garson Duane R. Reiss C. Meacham Harrell Kathy L. Murphy Joseph G. Bruno Rodney A. Bednar Wei Lemaire Donghui Cui Tamara D. Cabalu Cuyue Tang Thomayant Prueksaritanont George D. Hartman Steven D. Young Christopher J. Winrow John J. Renger Paul J. Coleman 《Bioorganic & medicinal chemistry letters》2013,23(24):6620-6624
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats. 相似文献
15.
Santora VJ Covel JA Hayashi R Hofilena BJ Ibarra JB Pulley MD Weinhouse MI Sengupta D Duffield JJ Semple G Webb RR Sage C Ren A Pereira G Knudsen J Edwards JE Suarez M Frazer J Thomsen W Hauser E Whelan K Grottick AJ 《Bioorganic & medicinal chemistry letters》2008,18(4):1490-1494
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model. 相似文献
16.
Chaudhary S Ponnala S Legendre O Gonzales JA Navarro HA Harding WW 《Bioorganic & medicinal chemistry》2011,19(19):5861-5868
A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT(2A) and α(1A) receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT(2A) and α(1A) antagonists, respectively. The C2 alkyloxy analogs studied were generally selective for α(1A) versus 5-HT(2A). The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT(2A) antagonists known presently. 相似文献
17.
R W Colman 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1991,197(3):242-248
This review highlights the increasing knowledge of the biochemistry, pathology, and cell and molecular biology of platelet receptors. A receptor for ADP has been identified using the affinity label FSBA as aggregin, a 100-kDa membrane protein responsible for shape change, aggregation, and exposure of fibrinogen binding sites. A variety of putative receptors for collagen have been described, with GPIa/IIa and GPIV receiving the most attention recently. A thromboxane A2 receptor has been identified using receptor antagonists and photoaffinity labels. The alpha 2-adrenergic receptor has been cloned and expressed. The platelet thrombin receptor has been tentatively identified as GPIb. Following binding of thrombin to this receptor, activation of calpain occurs, with cleavage of aggregin leading to exposure of GPIIb/III alpha and platelet aggregation. Isolation, expression, or both of the ADP, collagen, and thrombin receptors as single gene products of the human platelet responsible for activation, and more complete understanding of stimulus-response coupling, should allow for greater specificity of drugs with selective therapeutic actions. 相似文献
18.
Effect of selective muscarinic receptor agonists and antagonists on active-avoidance learning acquisition in rats 总被引:1,自引:0,他引:1
Effect of some selective muscarinic receptor agonists and antagonists was investigated on learning acquisition in an active-avoidance paradigm in rats which records an anticipatory conditioned avoidance apart from the classical conditioned avoidance response. The muscarinic M1 agonists, arecholine, pilocarpine and McN-A-343, facilitated learning acquisition, which was attenuated by the selective M1 antagonist, pirenzepine. On the other hand, M2 receptor agonist, carbachol, and physostigmine, induced a dose-related dual response, with lower doses retarding and higher doses facilitating the learning acquisition. The former effect was attenuated by gallamine, a muscarinic M2 antagonist, while the latter response was inhibited by pirenzepine, indicating that these putative M2 receptor agonist lose their receptor specificity on dose increment. The selective M2 receptor antagonists, gallamine and AF-DX 116, facilitated learning acquisition, which was inhibited by pirenzepine and the acetylcholine synthesis inhibitor hemicholinium. The results support the cholinergic hypothesis of learning and memory and indicate that M1 receptor agonists and M2 receptor antagonists are likely to prove beneficial in memory deficits. The data also indicates that the clinical dose of some drugs, like physostigmine, needs to be carefully established for optimum therapeutic benefit. 相似文献
19.
In a previous study we observed that most neurones in the paraventricular nucleus are excited by angiotensin-(1-7). In comparison with angiotensin III this excitatory action was significantly delayed. The aim of the present microiontophoretic study of angiotensin II-sensitive rat paraventricular neurones was to compare the effect of the angiotensin-analogues angiotensin-(1-7), angiotensin-(2-7), angiotensin II and angiotensin III on the spontaneous activity of these neurones and to test angiotensin receptor subtype 1 antagonists (CGP 46027 or DuP 753) and subtype 2 selective antagonists (CGP 42112A and PD 123177) in order to acquire more evidence of the receptor subtype present. As previously observed angiotensin II, angiotensin III and angiotensin-(1-7) excited most neurones. The effect of angiotensin-(1-7) was usually weaker than that of angiotensin II, and in contrast to angiotensin III the latencies were not significantly different. Angiotensin-(1-7) seemed to be active by itself, because its effect was antagonised by angiotensin receptor antagonists. Angiotensin-(2-7) was mostly inactive, although a few cells were excited. Whereas the excitatory effects of angiotensin-(1-7), angiotensin II and angiotensin III could always be inhibited with both angiotensin receptor subtype antagonists 1 and 2, that produced by angiotensin-(2-7) was only weakly antagonised, if at all. Subtype 1 selective antagonists were effective at lower concentrations than selective subtype 2 antagonists. 相似文献
20.
Design and synthesis of amidino-tyrosine derivatives as non-peptide fibrinogen receptor antagonists.
T L Xu X T Jiang W Y Hua P Z Ni Y M Pei 《Bioorganic & medicinal chemistry letters》1999,9(14):1933-1936
The design, synthesis and antiaggregation activity of amidino-tyrosine derivatives based on Arg-Gly-Asp (RGD) tripeptide sequence as non-peptide fibrinogen receptor antagonists is described. Optimization of the spacer and the substituent at the C-terminal is reported. 相似文献