共查询到20条相似文献,搜索用时 15 毫秒
1.
Bureau R Daveu C Lancelot JC Rault S 《Journal of chemical information and computer sciences》2002,42(2):429-436
A first definition of a pharmacophore for the serotonin reuptake inhibitors was carried out by considering a three-dimensional model which correlates the chemical structures of series of reuptake inhibitors with their biological affinities. A molecular design was described by analyzing two different 3D serotonin pharmacophores. This successful approach enabled us to consider the design of new serotonin ligands by the same method. 相似文献
2.
Lepailleur A Bureau R Lemaître S Dauphin F Lancelot JC Contesse V Lenglet S Delarue C Vaudry H Rault S 《Journal of chemical information and computer sciences》2004,44(3):1148-1152
A definition of a pharmacophore for the 5-HT7 antagonists was carried out by searching the common chemical features of selective antagonists from the literature. A molecular design is described by analyzing the differences between this new pharmacophore and three other 3D serotonin pharmacophores previously described. This comparison led to the synthesis of a new series of potent 5-HT7 antagonists. 相似文献
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María L. López-Rodríguez María José Morcillo Bellinda Benhamú María Luisa Rosado 《Journal of computer-aided molecular design》1997,11(6):589-599
The clinical use of currently available drugs acting at the5-HT4 receptor has been hampered by their lack of selectivityover 5-HT3 binding sites. For this reason, there is considerableinterest in the medicinal chemistry of these serotonin receptor subtypes, andsignificant effort has been made towards the discovery of potent and selectiveligands. Computer-aided conformational analysis was used to characterizeserotoninergic 5-HT3 and 5-HT4 receptorrecognition. On the basis of the generally accepted model of the5-HT3 antagonist pharmacophore, we have performed a receptormapping of this receptor binding site, following the active analog approach(AAA) defined by Marshall. The receptor excluded volume was calculated as theunion of the van der Waals density maps of nine active ligands(pKi 8.9), superimposed in pharmacophoric conformations.Six inactive analogs (pKi < 7.0) were subsequently used todefine the essential volume, which in its turn can be used to define theregions of steric intolerance of the 5-HT3 receptor. Five activeligands (pKi 9.3) at 5-HT4 receptors wereused to construct an antagonist pharmacophore for this receptor, and todetermine its excluded volume by superimposition of pharmacophoricconformations. The volume defined by the superimposition of five inactive5-HT4 receptor analogs that possess the pharmacophoric elements(pKi 6.6) did not exceed the excluded volume calculated forthis receptor. In this case, the inactivity may be due to the lack of positiveinteraction of the amino moiety with a hypothetical hydrophobic pocket, whichwould interact with the voluminous substituents of the basic nitrogen ofactive ligands. The difference between the excluded volumes of both receptorshas confirmed that the main difference is indeed in the basic moiety. Thus,the 5-HT3 receptor can only accommodate small substituents inthe position of the nitrogen atom, whereas the 5-HT4 receptorrequires more voluminous groups. Also, the basic nitrogen is located at ca.8.0 Å from the aromatic moiety in the 5-HT4 antagonistpharmacophore, whereas this distance is ca. 7.5 Å in the5-HT3 antagonist model. The comparative mapping of bothserotoninergic receptors has allowed us to confirm the three-componentpharmacophore accepted for the 5-HT3 receptor, as well as topropose a steric model for the 5-HT4 receptor binding site. Thisstudy offers structural insights to aid the design of new selective ligands,and the resulting models have received some support from the synthesis of twonew active and selective ligands: 24 (Ki(5-HT3)= 3.7 nM; Ki(5-HT4) > 1000 nM) and 25(Ki(5-HT4) = 13.7 nM;Ki(5-HT3) > 10 000 nM). 相似文献
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López-Rodríguez ML Benhamú B Murcia M Alvaro E Campillo M Pardo L 《Journal of computer-aided molecular design》2003,17(8):515-524
We report a structure-affinity analysis of an important element in the pharmacophore model for the recognition of 5-HT4 receptor antagonists: the voluminous substituent attached to the basic nitrogen of the ligand. We have designed, synthesized and pharmacologically evaluated a series of benzimidazole derivatives 1 containing a common molecular skeleton formed by N-[(4-piperidyl)methyl]-6-chlorobenzimidazole-4-carboxamide and four different substituents (R = butyl, 2-[(methylsulfonyl)amino]ethyl, 5-[(phenylacetyl)amino]pentyl, and 5-[(benzylsulfonyl)amino]pentyl). These compounds possess binding affinities in the nM range (Ki = 0.11-1.50 nM). Moreover, a ligand that contains a hydrogen atom attached to the basic nitrogen (R = H; Ki = 150 nM) is used as a control for structure-affinity relationships. 相似文献
7.
The 5-HT4 receptor (5-HT4R) agonists are important in treating gastrointestinal motility disorders. Their role is currently being evaluated for the treatment of cognitive and mood disorders. A selective 5-HT4R antagonist GR 125487 is used in many biological assays to cross confirm the 5-HT4R agonist’s activity. A practical synthesis of GR 125487 is developed so as to have it in desired quantities. The synthesis consists of seven steps starting from commercially available methyl 5-fluoroindole 3-carboxylate. The GR 125487 thus synthesized was used in blocking the activity of 5-HT4R agonist compound in animal models of cognition. 相似文献
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Melis C Chau PL Price KL Lummis SC Molteni C 《The journal of physical chemistry. B》2006,110(51):26313-26319
The 5-HT3 receptor is a typical ligand-gated ion channel of the Cys-loop superfamily, which is activated by binding of serotonin (5-HT). Models of the binding site of this protein reveal potential interactions between 5-HT and Tyr143, Tyr153, and Tyr234. Here we describe a series of ab initio calculations, based on density functional theory, to assess the effects of mutating these tyrosine residues on the binding of 5-HT. A series of mutations to these tyrosines, previously studied experimentally, were tested, and the binding energies compared with the available experimental data. Our results show that Tyr153 could form a hydrogen bond with the tertiary amine of 5-HT, and that mutation in this location revealed binding energies broadly in line with experimentally determined EC50s. Tyr143 could also form a hydrogen bond, but as EC50s do not relate to binding energies, it is unlikely that such a bond is formed here. Tyr234 is quite distinct in that it may interact with 5-HT via a mixed hydrogen bond/cation-pi interaction. 相似文献
10.
Lepailleur A Bureau R Paillet-Loilier M Fabis F Saettel N Lemaître S Dauphin F Lesnard A Lancelot JC Rault S 《Journal of chemical information and modeling》2005,45(4):1075-1081
The present study discusses the well-known 5-HT7/5-HT1A selectivity issue through a new series of phenylpyrrole derivatives. The first hits emerged from a virtual screening performed on a chemolibrary. Further study led to an optimization of a preliminary 5-HT7 pharmacophore model. The importance of each pharmacophoric feature is confirmed, but these characteristics have to be coupled to geometric constraints in order to achieve a 5-HT7 selectivity. Indeed, 5-HT1A affinity probably arises from extended conformations, whereas a bent one appears to be best suited for 5-HT7 selectivity. 相似文献
11.
Suzuki M Ohuchi Y Asanuma H Kaneko T Yokomori S Ito C Isobe Y Muramatsu M 《Chemical & pharmaceutical bulletin》2000,48(12):2003-2008
A series of N-azabicycloalkyl-1-alkyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized and tested for serotonin 5-HT4 receptor-stimulating effects in the regulation of electrically-evoked contraction in guinea pig muscle. Among them, N-azabicycloalkyl-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, 9c, 10c, 11c, 12c) exhibited potent serotonin 5-HT4 receptor-stimulating activity. The most potent compound, N-(endo-8-methyl-8-azabicyclo[3.2.1 oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, ED50 = 36.3 nMi), was seven times as active as cisapride, while 8c had no affinity for 5-HT1A, 5-HT1D, D2, muscarinic M2 or muscarinic M3 receptors even at 10 microM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.). 相似文献
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Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands. 相似文献
13.
The study of paramagnetic compounds based on 4d and 5d transition metals is an emerging research topic in the field of molecular magnetism. An essential driving force for the interest in this area is the fact that heavier metal ions introduce important attributes to the physical properties of paramagnetic compounds. Among the attractive characteristics of heavier elements vis-à-vis magnetism are the diffuse nature of their d orbitals, their strong magnetic anisotropy owing to enhanced spin-orbit coupling, and their diverse structural and redox properties. This critical review is intended to introduce readers to the topic and to report recent progress in this area. It is not fully comprehensive in scope although we strived to include all relevant topics and a large subset of references in the area. Herein we provide a survey of the history and current status of research that has been conducted on the topic of second and third row transition metal molecular magnetism. The article is organized according to the nature of the precursor building blocks with special topics being highlighted as illustrations of the special role of heavier transition metal ions in the field. This paper is addressed to readers who are interested in molecular magnetism and the application of coordination chemistry principles to materials synthesis (231 references). 相似文献
14.
Bronowska A Chilmonczyk Z Leś A Edvardsen O Ostensen R Sylte I 《Journal of computer-aided molecular design》2001,15(11):1005-1023
In the present study experimentally determined ligand selectivity of three methylated buspirone analogues (denoted as MM2, MM5 and P55) towards 5-HT1A and 5-HT2A serotonin receptors was theoretically investigated on a molecular level. The relationships between the ligand structure and 5-HT1A and 5-HT2A receptor affinities were studied and the results were found to be in agreement with the available site-directed mutagenesis and binding affinity data. Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT1A/5-HT2A, each time in a different orientation. Present results were compared with our previous theoretical results, obtained for buspirone and its non-methylated analogues. It was found that due to the presence of the methyl group in the piperazine ring the ligand position alters and the structure of the ligand-receptor complex is modified. Further, the positions of derivatives with pyrimidinyl aromatic moiety and quinolinyl moiety are significantly different at the 5-HT2A receptor. Thus, methylation of such derivatives alters the 3D structures of ligand-receptor complexes in different ways. The ligand-induced changes of the receptor structures were also analysed. The obtained results suggest, that helical domains of both receptors have different dynamical behaviour. Moreover, both location and topography of putative binding sites for buspirone analogues are different at 5-HT1A and 5-HT2A receptors. 相似文献
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A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor. 相似文献
16.
Abbas Shockravi Hassan Valizadeh Majid. M. Heravi 《Phosphorus, sulfur, and silicon and the related elements》2013,188(12):2835-2841
4-Substituted coumarins were efficiently and rapidly synthesised via Pechmann condensation of phenols with ethyl acetoacetate catalyzed by P 2 O 5 /molecular sieves in satisfactory yields. 相似文献
17.
Seeber M De Benedetti PG Fanelli F 《Journal of chemical information and computer sciences》2003,43(5):1520-1531
Comparative molecular dynamics simulations of the 5-HT(1A) receptor in its empty as well as agonist- (i.e. active) and antagonist-bound (i.e. nonactive) forms have been carried out. The agonists 5-HT and (R)-8-OH-DPAT as well as the antagonist WAY100635 have been employed. The results of this study strengthen the hypothesis that the receptor portions close to the E/DRY/W motif, with prominence to the cytosolic extensions of helices 3 and 6, are particularly susceptible to undergo structural modification in response to agonist binding. Despite the differences in the structural/dynamics behavior of the two agonists when docked into the 5-HT(1A) receptor, they both exert a destabilization of the intrahelical and interhelical interactions found in the empty and antagonist-bound receptor forms between the arginine of the E/DRY sequence and both D133(3.49) and E340(6.30). For both agonists, the chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor, such as D116(3.32), S199(5.42), Y195(5.38), and F361(6.51). A significant reduction in the bend at P360(6.50), as compared to the empty and the antagonist-bound receptor forms, is one of the features of the agonist-bound forms that is related to the breakage of the interhelical salt bridge between the E/DRY arginine and E340(6.30). Another structural feature, shared by the agonist-bound receptor forms and not by the empty and antagonist-bound forms, is the detachment of helices 2 and 4, as marked by the movement of W161(4.50) away from helix 2, toward the membrane space. 相似文献
18.
Suzuki M Ohuchi Y Asanuma H Kaneko T Yokomori S Ito C Isobe Y Muramatsu M 《Chemical & pharmaceutical bulletin》2001,49(1):29-39
A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction. 相似文献
19.
P糖蛋白(P-glycoprotein,Pgp)和细胞色素P4503A4(CYP3A4)是决定药物ADME性质的两个重要蛋白,目前还无法通过实验方法,从分子水平清晰阐明这两个蛋白采取怎样的互补作用机理来降低外来药物的生物利用度.通过3D-药效团模建方法,提取Pgp和CYP3A4的共同底物的特征阐明这两个蛋白可能的协同作用模式.所得的药效团有助于理解药物分子同这两个蛋白的作用模式,同时该模型可以指导新药设计和改造,从而提高药物的生物利用度. 相似文献