共查询到20条相似文献,搜索用时 15 毫秒
1.
It is thought that selective 5-HT(4) receptor agonists-such as 4-amino-5-chloro-2-methoxy-N-[1-(6-oxo-6-phenylhexyl)piperidin-4ylmethyl]benzamide (2)-have the ability to enhance both upper and lower gastrointestinal motility without any significant adverse effects. Modification of 2 was performed. Variation of the piperidin-4ylmethyl moiety of 2 led to a decrease in the binding affinity for the 5-HT(4) receptor. Following conversion of the carbonyl group on the benzoyl part to a hydroxyl or sulfoxide group, the binding affinity for the 5-HT(4) receptor was retained although the effect on defecation was reduced. Many of the 4-amino-5-chloro-2-methoxy-N-(piperidin-4ylmethyl)benzamides that had a ether or sulfide moiety in the side-chain part at the 1-position of the piperidine exhibited high affinity for the 5-HT(4) receptor. Among these, phenylthio 41c and benzylthio derivative 44 were selective 5-HT(4) receptor agonists, and had a similar effect on defecation to compound 2. 相似文献
2.
R. Murray McKinnell Scott R. Armstrong David T. Beattie Paul R. Fatheree Daniel D. Long Daniel G. Marquess Jeng-Pyng Shaw Ross G. Vickery 《Bioorganic & medicinal chemistry letters》2013,23(14):4210-4215
The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species. 相似文献
3.
Pyrrolizidine benzamide (+/-)-2, the bridgehead-methyl analog of SC-53116, was prepared and evaluated for 5-HT(4) agonism activity in the rat tunica muscularis (TMM) mucosae assay. Compound (+/-)-2 has an EC(50) of 449 nM in the TMM assay, as compared to 23 nM for SC-53116, and 66 nM for the racemate of SC-53116. 相似文献
4.
Joubert L Claeysen S Sebben M Bessis AS Clark RD Martin RS Bockaert J Dumuis A 《The Journal of biological chemistry》2002,277(28):25502-25511
Activation of G protein-coupled receptors is thought to involve disruption of intramolecular interactions that stabilize their inactive conformation. Such disruptions are induced by agonists or by constitutively active mutations. In the present study, novel potent inverse agonists are described to inhibit the constitutive activity of 5-HT(4) receptors. Using these compounds and specific receptor mutations, we investigated the mechanisms by which inverse agonists may reverse the disruption of intramolecular interactions that causes constitutive activation. Two mutations (D100(3.32)A in transmembrane domain (TMD)-III and F275(6.51)A in TMD-VI) were found to completely block inverse agonist effects without impairing their binding properties nor the molecular activation switches induced by agonists. Based on the rhodopsin model, we propose that these mutated receptors are in equilibrium between two states R and R* but are unable to reach a third "silent" state stabilized by inverse agonists. We also found another mutation in TMD-VI (W272(6.48)A) that stabilized this silent state. This mutant remained fully activated by agonists. Molecular modeling indicated that Asp-100, Phe-275, and Trp-272 might constitute a network required for stabilization of the silent state by the described inverse agonists. However, this network is not necessary for agonist activity. 相似文献
5.
Chai W Chan KY de Vries R van den Bogeardt AJ de Maeyer JH Schuurkes JA Villalón CM Saxena PR Danser AH MaassenVanDenBrink A 《Life sciences》2012,90(13-14):538-544
AimsBesides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine4 (5-HT4) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT4 receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT3 receptor agonist MKC773 on human isolated myocardial trabeculae, and compared their effects with those induced by 5-HT and 5-methoxytryptamine (5-MeOT).Main methodsAtrial and ventricular trabeculae were paced and changes in contractile force were studied in the absence or presence of the 5-HT4 receptor antagonist GR113808. Partial agonism was assessed using 5-HT4 receptor agonists as antagonists against 5-HT. To test the contribution of L-type calcium channels, the inotropic responses to 5-HT and 5-MeOT were studied in the absence or presence of verapamil.Key findingsLike 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC733, induced concentration-dependent positive inotropic responses on atrial trabeculae, which were abolished by GR113808. The L-type calcium channel blocker verapamil attenuated inotropic responses to 5-HT and 5-MeOT. None of the agonists affected the contraction of left ventricular trabeculae. Concentration response curves to 5-HT were shifted to the right in the presence of prucalopride, cisapride, tegaserod and R199715, but not MKC-773.SignificanceWe conclude that (i) inotropic responses to 5-HT and 5-MeOT seem to depend on L-type calcium channels, (ii) tegaserod and cisapride behave as partial 5-HT4 receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT4 receptor antagonist. 相似文献
6.
Synthesis and pharmacological properties of benzamide derivatives as selective serotonin 4 receptor agonists 总被引:1,自引:0,他引:1
Sonda S Katayama K Kawahara T Sato N Asano K 《Bioorganic & medicinal chemistry》2004,12(10):2737-2747
A series of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamides with a polar substituent group at the 1-position of the piperidine ring was synthesized and evaluated for its effect on gastrointestinal motility. The benzoyl, phenylsulfonyl, and benzylsulfonyl derivatives accelerated gastric emptying and increased the frequency of defecation. One of them, 4-amino-N-[1-[3-(benzylsulfonyl)propyl]piperidin-4-ylmethyl]-5-chloro-2-methoxybenzamide (13a, Y-36912), was a selective 5-HT4 receptor agonist offering potential as a novel prokinetic with reduced side effects derived from 5-HT3- and dopamine D2 receptor-binding affinity. In the oral route of administration, this compound enhanced gastric emptying and defecation in mice, and has a possibility as a prokinetic agent, which is effective on both the upper and the lower gastrointestinal tract. 相似文献
7.
Charlotte M.N. Allerton Mark D. Andrews Julian Blagg David Ellis Edel Evrard Martin P. Green Kevin K.-C. Liu Gordon McMurray Michael Ralph Vivienne Sanderson Robin Ward Lesa Watson 《Bioorganic & medicinal chemistry letters》2009,19(19):5791-5795
The SAR of a series of pyridazinone derived 5-HT2C agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT2C functional agonism and selectivity over 5-HT2A and 5-HT2B. This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration. 相似文献
8.
Daniel L. Flynn Daniel P. Becker Dale P. Spangler Roger Nosal Gary W. Gullikson Chafiq Moummi Dai-Chang Yang 《Bioorganic & medicinal chemistry letters》1992,2(12):1613-1618
New aza(nor)adamantanes
,
, and
are described which exhibit properties of both 5-HT4 agonism and 5-HT3 antagonism. In particular, compound
[SC-52491], an azanoradamantane, exhibits an EC50 of 51 nM in a functional model of 5-HT4 agonism and potent antagonism, Ki = 1.2 nM, at the 5-HT3 receptor. 相似文献
9.
Bentley JM Adams DR Bebbington D Benwell KR Bickerdike MJ Davidson JE Dawson CE Dourish CT Duncton MA Gaur S George AR Giles PR Hamlyn RJ Kennett GA Knight AR Malcolm CS Mansell HL Misra A Monck NJ Pratt RM Quirk K Roffey JR Vickers SP Cliffe IA 《Bioorganic & medicinal chemistry letters》2004,14(9):2367-2370
A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration. 相似文献
10.
《Life sciences》1987,41(9):1077-1081
The effects of the 5-HT2-sselective agonists 1-(4-bromo-2, 5-dimethoxyphenyl) -2- aminopropane (DOB) and 1- (2, 5-dimethenyl4-iodophenyl) -2- aminopropane (DOI) on cat platelet aggregation were investigated and compared with those produced by serotonin (5-HT) and a positional isomer of DOB (i.e., isoDOB). Serotonin, DOB, and DOI enhanced the aggregation of platelets induced by a suboptimal concentration of ADP. This effect was completely inhibited by pre-incubation of the platelet suspension with the 5-HT2-selective antagonist ketanserin. IsoDOB, an isomer of DOB with a very low affinity for central 5-HT2 binding sites, was inactive in the platelet aggregation assay. The present results are consistent with the proposed role of 5-HT2 receptors in serotonin-induced platelet aggregation 相似文献
11.
Slassi A Edwards L O'Brien A Meng CQ Xin T Seto C Lee DK MacLean N Hynd D Chen C Wang H Kamboj R Rakhit S 《Bioorganic & medicinal chemistry letters》2000,10(15):1707-1709
A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine. 相似文献
12.
Röver S Adams DR Bénardeau A Bentley JM Bickerdike MJ Bourson A Cliffe IA Coassolo P Davidson JE Dourish CT Hebeisen P Kennett GA Knight AR Malcolm CS Mattei P Misra A Mizrahi J Muller M Porter RH Richter H Taylor S Vickers SP 《Bioorganic & medicinal chemistry letters》2005,15(15):3604-3608
Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists. 相似文献
13.
Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action 总被引:6,自引:0,他引:6
Lucas G Rymar VV Du J Mnie-Filali O Bisgaard C Manta S Lambas-Senas L Wiborg O Haddjeri N Piñeyro G Sadikot AF Debonnel G 《Neuron》2007,55(5):712-725
Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action. 相似文献
14.
Silvia Franchini Adolfo Prandi Claudia Sorbi Annalisa Tait Annamaria Baraldi Piero Angeli Michela Buccioni Antonio Cilia Elena Poggesi Paola Fossa Livio Brasili 《Bioorganic & medicinal chemistry letters》2010,20(6):2017-2020
Starting from compounds previously identified as α1-adrenoceptor antagonists that were also found to bind to the 5-HT1A receptor, in an attempt to separate the two activities, a new series of 5-HT1A receptor agonists was identified and shown to have high potency and/or high selectivity. Of these, compound 13, which combines high selectivity (5-HT1A/α1 = 151) and good agonist potency (pD2 = 7.82; Emax = 76), was found to be the most interesting. 相似文献
15.
Andreas Nievergelt Peter Huonker Roland Schoop Karl-Heinz Altmann Jürg Gertsch 《Bioorganic & medicinal chemistry》2010,18(9):3345-3351
Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT1A receptor with significant to moderate binding affinities (Ki = 3–20 μΜ). [35S]-GTPγS assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (Ki = 11.6 μg/ml) partially activate the 5-HT1A receptor (20–60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT1A active compounds. 相似文献
16.
Meng CQ Rakhit S Lee DK Kamboj R McCallum KL Mazzocco L Dyne K Slassi A 《Bioorganic & medicinal chemistry letters》2000,10(9):903-905
A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine. 相似文献
17.
Possible involvement of 5-HT and 5-HT2 receptors in acceleration of gastrointestinal transit by escin Ib in mice 总被引:4,自引:0,他引:4
We have reported previously that escin Ib accelerated gastrointestinal transit (GIT) in mice, and that its effect may be mediated by the release of endogenous prostaglandins (PGs) and nitric oxide (NO). In this study, the possible involvement of 5-HT and 5-HT receptors in the GIT acceleration of escin Ib was investigated in mice. The acceleration of GIT by escin Ib (25 or 50 mg/kg, p.o.) was attenuated by pretreatment with ritanserin (0.5-5 mg/kg, s.c., a 5-HT(2A/2C/2B) receptor antagonist), but not with MDL 72222 (1 and 5 mg/kg, s.c.) and metoclopramide (10 mg/kg, s.c.) (5-HT3 receptor antagonists) or tropisetron (1 and 10 mg/kg, s.c., a 5-HT(3/4) receptor antagonist). Furthermore, pretreatment with ketanserin (0.05-5 mg/kg, s.c.), haloperidol (1-5 mg/kg, s.c.) and spiperone (0.5-5 mg/kg, s.c.) (5-HT2A receptor antagonists), as well as a bolus of dl-p-chlorophenylalanine methyl ester (PCPA, 1000 mg/kg, p.o., 1, 6 or 24 h before administration of the sample) (an inhibitor of 5-HT synthesizing enzyme tryptophan hydroxylase) and reserpine (5 mg/kg, p.o.) (a 5-HT depletor), but not 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor) or repeated PCPA (300 mg/kg x2, p.o., 72 and 48 h before administration of the sample), also attenuated the effects of escin Ib. It is postulated that escin Ib accelerates GIT, at least in part, by stimulating the synthesis of 5-HT to act through 5-HT2, possibly 5-HT2A receptors, which in turn causes the release of NO and PGs. 相似文献
18.
Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT 2A receptors. The (+/-)phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT 2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)- and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies. In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT 2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered. 相似文献
19.
Clement Q. Fontenelle Zhong Wang Christine Fossey Thomas Cailly Bruno Linclau Frederic Fabis 《Bioorganic & medicinal chemistry》2013,21(23):7529-7538
Analogues of potent 5-HT4R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine’s nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT4R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors. 相似文献
20.
Mattsson C Sonesson C Sandahl A Greiner HE Gassen M Plaschke J Leibrock J Böttcher H 《Bioorganic & medicinal chemistry letters》2005,15(19):4230-4234
A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT6 activity. The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole with an IC50=7.4 nM in 3H-LSD binding and an EC50=1.0 nM in a functional assay measuring production of cyclic AMP. 相似文献