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1.
Kenakin T 《Molecular interventions》2004,4(4):222-229
Allosteric antagonists modulate the affinity and/or efficacy of agonists for receptors. Although the manner in which this modulation can occur can mimic that of simple competitive antagonists, allosteric antagonists possess unique properties that can present seemingly capricious profiles of antagonism. These unique properties also offer potentially useful patterns for therapeutic utility. This review summarizes methods to detect allosteric antagonism and some special properties of these receptor modulators. 相似文献
2.
Antagonistic and agonistic activities of backbone cyclic (BBC) pheromone biosynthesis activating neuropeptide (PBAN) analogues were evaluated in an attempt to identify potent melanotropic antagonists, to gain an insight into their structure-activity relationship (SAR), and to discover molecules with selective and non-selective melanotropic and pheromonotropic properties. Eight potent melanotropic BBC antagonists and seven agonists were disclosed. SAR studies revealed that the structural requirements of the melanotropic and pheromonotropic agonists and antagonists are different. The cyclic structure of the BBC peptides was unimportant for antagonistic activity, and linearization retained their melanotropic and pheromonotropic antagonistic properties. Comparison of the antagonistic activities of the BBC and precyclic peptides with respect to both functions revealed eight selective antagonists (six that were selective melanotropic antagonists and two selective pheromonotropic antagonists) and four non-selective (melanotropic and pheromonotropic) antagonists. The selective melanotropic antagonists exhibited both, pure or mixed agonistic/antagonistic activities. The selective pheromonotropic compounds were pure antagonists. All non-selective compounds were pure antagonists. Comparison of the agonistic activities of the BBC peptides with respect to both functions revealed six selective melanotropic agonists and one non-selective agonistic compound. All compounds (whether selective or non-selective) exhibited pure agonistic activity. Discovery of the selective compounds hints at the possibility that the receptors that mediate the respective activities may have different properties. 相似文献
3.
Sakaki J Konishi K Kishida M Gunji H Kanazawa T Uchiyama H Fukaya H Mitani H Kimura M 《Bioorganic & medicinal chemistry letters》2007,17(17):4808-4811
Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties. 相似文献
4.
E. M. van der Wenden P. J.M. van Galen A. P. Ijzerman W. Soudijn 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1199-1200
Abstract Adenosine A, antagonists cause, among other effects, stimulation of the central nervous system, renal vasodilatation and facilitation of the atrio-ventricular conduction. These possible applications call for an examination of the antagonist properties, in order to develop newer and more selective antagonists. 相似文献
5.
Ionotropic glutamate receptors antagonists are now widely considered as potential medications for a variety of disorders, such as seizures, neurodegenerative diseases, stroke, and opiate tolerance and dependence. There is a growing body of evidence suggesting that the safest drugs are to be found amongst antagonists acting at glycine and polyamine sites of NMDA-receptor complex, low-affinity channel blockers, subtype-selective competitive NMDA-receptor antagonists, as well as non-NMDA glutamate receptors antagonists. These antagonists exhibit little or no abuse liability and are less likely to induce phencyclidine-like attention deficits and disruption of sensomotor gating. Meanwhile, these drugs retain most of the potentially useful properties, including anxiolytic and antidepressant effects. 相似文献
6.
Chen X Mihalic J Fan P Liang L Lindstrom M Wong S Ye Q Fu Y Jaen J Chen JL Dai K Li L 《Bioorganic & medicinal chemistry letters》2012,22(1):363-366
A series of spiropiperidine carbazoles were synthesized and evaluated as MCHR2 antagonists using a FLIPR assay. The pharmacokinetic properties of selected compounds have also been studied. This effort led to the discovery of potent and specific MCHR2 antagonists. Compound 38 demonstrated good pharmacokinetic properties across rat, beagle dog and rhesus monkey and had a favorable selectivity profile against a number of other receptors. These MCHR2 antagonists are considered appropriate tool compounds for study of the function of MCHR2 in vivo. 相似文献
7.
Simon Peace Joanne Philp Carl Brooks Val Piercy Kitty Moores Chris Smethurst Steve Watson Simon Gaines Mara Zippoli Claudette Mookherjee Robert Ife 《Bioorganic & medicinal chemistry letters》2010,20(13):3961-3964
A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pKa, yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma. 相似文献
8.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Kim Brackenborough Michael A. Briggs Stephen Brough Andrew R. Calver Barry Crook Rebecca K. Davis Robert P. Davis Susannah Davis David K. Dean Leanne Harris Teresa Heslop Vicky Holland Phillip Jeffrey Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6890-6896
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer’s disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties. 相似文献
9.
Petzer JP Steyn S Castagnoli KP Chen JF Schwarzschild MA Van der Schyf CJ Castagnoli N 《Bioorganic & medicinal chemistry》2003,11(7):1299-1310
Adenosine receptor antagonists that are selective for the A(2A) receptor subtype (A(2A) antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A(2A) antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A(2A) antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A(2A) antagonists examined display significant MAO-B inhibitory properties in vitro with K(i) values in the low micro M to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A(2A) antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A(2A) receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD. 相似文献
10.
Shankaran K Donnelly KL Shah SK Guthikonda RN MacCoss M Mills SG Gould SL Malkowitz L Siciliano SJ Springer MS Carella A Carver G Hazuda D Holmes K Kessler J Lineberger J Miller MD Emini EA Schleif WA 《Bioorganic & medicinal chemistry letters》2004,14(13):3419-3424
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed. 相似文献
11.
The influence of physical and chemical properties of some sites of transmembrane receptor domains on the receptors ability to interact with nonspecific antagonists was investigated mathematically. The properties of sites located in 3rd and 7th transmembrane domains are most likely to explain pharmacological characteristics of the receptors. The possibility of receptor blocking by nonspecific antagonists not by competing with agonists but by influencing the receptor conformation is discussed. 相似文献
12.
Ellsworth BA Wang Y Zhu Y Pendri A Gerritz SW Sun C Carlson KE Kang L Baska RA Yang Y Huang Q Burford NT Cullen MJ Johnghar S Behnia K Pelleymounter MA Washburn WN Ewing WR 《Bioorganic & medicinal chemistry letters》2007,17(14):3978-3982
Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose. 相似文献
13.
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
14.
F Svec 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1991,198(3):811-817
The initial goal of this work was to examine directly the properties of glucocorticoid receptors bound with antagonists. Cortexolone, progesterone, and R-5020 were the antagonists studied. The tritiated agonists, dexamethasone and triamcinolone acetonide, served as controls. Although the three antiglucocorticoids interfered with agonist binding to the glucocorticoid receptor, direct binding of the tritiated antagonists could not be reproducibility demonstrated using either a charcoal assay or rapid techniques like high performance liquid chromatography or vertical tube rotor ultracentrifugation. Ultraviolet radiation was used to attach covalently tritiated steroid to the receptor. This technique allowed the identification of species that bound agonist or antagonist. That the two classes of steroids bound to the same receptor was shown using a monoclonal antibody directed against the glucocorticoid receptor. These labeled species had the same physical properties upon ultracentrifugation, DEAE cellulose chromatography, and high performance liquid chromatography. It is concluded that although the interaction of antiglucocorticoids like progesterone with the glucocorticoid receptor may be fleeting, antagonists do interact with the glucocorticoid receptor and form complexes with grossly similar properties as those derived from an interaction with agonists. 相似文献
15.
Mark A. Hilfiker Ning Wang Xiaoping Hou Zhimin Du Mark A. Pullen Melanie Nord Rakesh Nagilla Harvey E. Fries Charlene W. Wu Anthony C. Sulpizio Jon-Paul Jaworski Dwight Morrow Richard M. Edwards Jian Jin 《Bioorganic & medicinal chemistry letters》2009,19(15):4292-4295
This Letter discloses a series of 2-aminothiadiazole amides as selective EP3 receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP3 receptor antagonists with excellent DMPK properties suitable for in vivo studies. 相似文献
16.
Li AR Johnson MG Liu J Chen X Du X Mihalic JT Deignan J Gustin DJ Duquette J Fu Z Zhu L Marcus AP Bergeron P McGee LR Danao J Lemon B Carabeo T Sullivan T Ma J Tang L Tonn G Collins TL Medina JC 《Bioorganic & medicinal chemistry letters》2008,18(2):688-693
A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo. 相似文献
17.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Michael A. Briggs Andrew R. Calver Barry Crook Robert P. Davis Susannah Davis David K. Dean Leanne Harris Tom D. Heightman Terry Panchal Christopher A. Parr Nigel Quashie Jon G.A. Steadman Joanne Schogger Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6897-6901
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. 相似文献
18.
Guanine nucleotides modulate the affinity of antagonists at beta-adrenergic receptors 总被引:4,自引:0,他引:4
Investigation of the properties of the binding of the radiolabelled antagonists (125I)-iodohydroxybenzylpindolol, (125I)-iodopindolol, and (125I)-iodocyanopindolol to beta-adrenergic receptors of L6 myoblast membranes revealed that guanine nucleotides caused a 2 to 4.5 fold increase in the apparent affinity of these antagonists. No significant effects of GTP were observed on the density of binding sites determined with each radioligand. GTP, GDP, and GMPPNP were of similar high affinity in producing this effect, while GMP was much less potent, and ATP was without effect. Under similar assay conditions GTP reduced the apparent binding affinity of the agonist isoproterenol for the beta-adrenergic receptors of L6 cells. The results indicate that, contrary to previous observations, guanine nucleotides affect not only the interactions of agonists with beta-adrenergic receptors, but also the interaction of antagonists with these adenylate cyclase-linked receptors. 相似文献
19.
Xiong Y Ullman B Choi JS Cherrier M Strah-Pleynet S Decaire M Feichtinger K Frazer JM Yoon WH Whelan K Sanabria EK Grottick AJ Al-Shamma H Semple G 《Bioorganic & medicinal chemistry letters》2012,22(5):1870-1873
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation. 相似文献
20.
Gomtsyan A Bayburt EK Keddy R Turner SC Jinkerson TK Didomenico S Perner RJ Koenig JR Drizin I McDonald HA Surowy CS Honore P Mikusa J Marsh KC Wetter JM Faltynek CR Lee CH 《Bioorganic & medicinal chemistry letters》2007,17(14):3894-3899
SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain. 相似文献