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Selective Ligands (selective + ligand)
Selected AbstractsThe Discovery of Tetrahydrofluorenones as a New Class of Estrogen Receptor ,-Subtype Selective Ligands.CHEMINFORM, Issue 38 2006R. R. Wilkening Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] ChemInform Abstract: Pyrrolylquinoxalinediones Carrying a Piperazine Residue Represent Highly Potent and Selective Ligands to the Homomeric Kainate Receptor GluR5.CHEMINFORM, Issue 49 2002W. Lubisch Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] HTS and Rational Drug Design to Generate a Class of 5-HT2C -Selective Ligands for Possible Use in Schizophrenia.CHEMMEDCHEM, Issue 8 2010Treating neurological conditions: Optimization of a previously identified lead 5-HT2C agonist (left) led to the discovery of a highly selective 5-HT2C agonist (right). Importantly, this compound is a 5-HT2B receptor antagonist. Because of its selective 5-HT2C receptor activity, the compound was further evaluated in the phencyclidine model of disrupted prepulse inhibition, and found to exhibit normalizing effects comparable to those shown by the 5-HT2C agonist vabicaserin, a drug currently in phase,II clinical studies for schizophrenia. [source] Highly Efficient and Versatile Phosphine-Phosphoramidite Ligands for Asymmetric HydrogenationADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 5 2009Matthias Eggenstein Abstract A set of novel phosphine-phosphoramidite ligands possessing two elements of chirality have been prepared through a modular synthetic approach. The ligands (11bS)- N -[2-(diphenylphosphino)phenyl]- N -[(S)-1-phenylethyl]dinaphtho[2,1- d:1,,2,- f][1,3,2]dioxaphosphepin-4-amine [(Sa,Sc)- 1a] and (11bR)- N -[2-(diphenylphosphino)phenyl]- N -[(S)-1-(1-naphthyl)ethyl]dinaphtho[2,1- d:1,,2,- f][1,3,2]dioxaphosphepin-4-amine [(Sa,Sc)- 1b] are unique in providing enantioselectivities ,96% ee and ,94% ee, respectively, in mechanistically distinct hydrogenations of CC, CN and CO double bonds in combination with three different transition metals (rhodium, iridium, and ruthenium, respectively). Particularly remarkable are the enantiomeric excesses up to 97% achieved in the iridium-catalyzed hydrogenation of 2-substituted quinolines, where (11bS)- N -[2-(diphenylphosphino)phenyl]- N -[(S)-1-(naphthalen-1-yl)ethyl]-8,9,10,11, 12,13,14,15-octahydrodinaphtho[2,1- d:1,,2,- f][1,3,2]dioxaphosphepin-4-amine [(Sa,Sc)- 2] proved to be the most selective ligand. Substantially lower ees were obtained with the mismatched diastereomer (Ra,Sc)- 1b and with the N -phenyl-substituted ligand 1c, missing a second element of chirality. [source] Estrogens inhibit l -glutamate uptake activity of astrocytes via membrane estrogen receptor ,JOURNAL OF NEUROCHEMISTRY, Issue 6 2003Kaoru Sato Abstract We investigated the effects of estrogen-related compounds including xenoestrogens [17,-estradiol (E2), 17,-ethynylestradiol (EE), diethylstilbestrol (DES), p-nonylphenol (PNP), bisphenol A (BPA) and 17,-estradiol (17,)] on l -glu uptake by cultured astrocytes via glutamate-aspartate transporter (GLAST). After 24 h treatment, E2 inhibited the l -glu uptake at 1 µm and higher concentrations. EE and DES also inhibited the l -glu uptake at 1 nm and higher concentrations. The other four compounds had no effect. The effects of E2, EE and DES were completely blocked by 10 nm of ICI182 780 (ICI). ,-Estradiol 17-hemisuccinate : bovine serum albumin (E2-BSA), a membrane-impermeable conjugate of E2, also elicited the inhibition of l -glu uptake at 1 nm and higher concentrations, and the effect was blocked by ICI. 16,-Iodo-17,-estradiol (16,IE2), an estrogen receptor , (ER,) selective ligand, revealed an inhibitory effect at 10 nm, while genistein, an ER, selective ligand, failed to reveal such an effect at this concentration. Western blot analysis showed that the predominant ER of cultured astrocytes was ER,. The colocalization of ER, with GLAST on plasma membranes was immunohistochemically detected in these cells. From these results, we concluded that estrogens down-regulate l -glu uptake activity of astrocytes via membrane ER,. [source] The design of a new potent and selective ligand for the orphan bombesin receptor subtype 3 (BRS3)JOURNAL OF PEPTIDE SCIENCE, Issue 3 2005Robert G. Boyle Abstract Extensive SAR studies on the unselective BRS3 agonist, [H-D-Phe6,,-Ala11,Phe13,Nle14]-bombesin-(6-14)-nonapeptide amide, have highlighted structural features important for BRS3 activity and have provided guidance as to the design of selective agonists. A radically modified heptapeptide agonist, maintaining only the Trp-Ala moiety of the parent [H-D-Phe6,,Ala11,Phe13,Nle14]-peptide amide, and with a very different carboxyl terminal region, has been produced which was potent at BRS3 and essentially had no NMB or GRP receptor activity. Its structure is Ac-Phe-Trp-Ala-His(,Bzl)-Nip-Gly-Arg-NH2. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structuresACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009Takuji Oyama Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPAR, and PPAR, LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD,ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPAR, LBD in complex with an ,/,-selective ligand, TIPP-401, and with a related ,-specific ligand, TIPP-204, were also determined. The comparison between the two PPAR, complexes revealed how each ligand exhibits either a `dual selective' or `single specific' binding mode. [source] A multiparameter flow cytometric analysis of the effect of bexarotene on the epidermis of the psoriatic lesionBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2003M.E.J. Franssen Summary Background A new retinoid, bexarotene (Targretin®), was recently investigated in a large multicentre trial for its efficacy and safety in psoriasis. Bexarotene is a novel retinoid X receptor (RXR)-selective ligand. Objectives The aim was to study the effect of bexarotene in psoriasis by analysing markers for epidermal differentiation, proliferation and inflammation in epidermal single cell suspensions from lesions of patients with psoriasis treated with various doses of bexarotene. Methods Thirty-four patients with moderate to severe plaque psoriasis participated in this study and were assigned in sequence to four different dose regimens: 0·5, 1, 2 and 3 mg kg,1 once daily. Before and after 12 weeks of bexarotene treatment, punch biopsies were taken from lesional skin from which epidermal single cell suspensions were prepared using an optimized thermolysin protocol. A sum of scores was determined for each biopsy site, based on a four-point scale for erythema, induration and desquamation. An improved multiparameter flow cytometric assay was used that enabled simultaneous assessment of epidermal proliferation, various aspects of differentiation and epidermal inflammation. The following variables were measured simultaneously: relative DNA content, relative cell size, keratin (K) 10, K6 and vimentin expression. Results The psoriasis area and severity index (PASI) and sum of scores for the individual psoriatic lesion each showed a statistically significant decrease of 28% after 12 weeks of bexarotene treatment (P < 0·001). However, no significant dose,response effect was found. The total percentage of K10+ cells showed a significant increase of 43% (P < 0·01). The total population of K6 expressing cells did not show significant changes. Regarding the subpopulations of K6 single, K10 single and K6 and 10 co-expressing cells, a significant increase of 77% was seen in the K10+ K6, cells (P < 0·05), a significant decrease of 33% in K10, K6+ cells (P < 0·01), and no significant changes in the remaining population of K10+ K6+ cells. After 12 weeks of treatment with bexarotene no significant changes in epidermal proliferation and inflammation were shown. Conclusions The present study indicates a direct effect of RXR activation by bexarotene on the transition of proliferation-associated keratinization into normal keratinization. Although no direct effect of bexarotene on DNA content in the total K10, cells was shown, further studies on subpopulations within the germinative layer such as stem cells and transit amplifying cells might be worthwhile. [source] A Cascade FRET-Mediated Ratiometric Sensor for Cu2+Ions Based on Dual Fluorescent Ligand-Coated Polymer NanoparticlesCHEMISTRY - A EUROPEAN JOURNAL, Issue 33 2009Michel Frigoli Dr. Abstract Core-shell type dual fluorescent nanoparticles (NPs) in the 16,nm diameter range with a selective ligand (cyclam) attached to the surface and two fluorophores,9,10-diphenyl-anthracene (donor, D) and pyrromethene PM,567 (acceptor, A),embedded within the polymer core were synthesized and their fluorescent and copper-sensing properties were studied and compared to single D -doped and A -doped NPs. The acceptor (A) and donor (D) dyes were chosen to allow two sequential Förster resonance energy transfer (FRET) processes from D to A and from the encapsulated dyes to copper complexes that form at the surface and act as quenchers. NPs with different D/A loads were readily obtained by two consecutive entrapments of the dyes. Dual NPs present tunable fluorescence emission that is dependent on the doping ratio. FRET from D to A results in sensitized emission from A upon excitation of D, with FRET efficiencies reaching 80,% at high acceptor loads. A 9-fold amplification of the signal of A is observed at high D -to- A ratios. Single- and dual-dye-doped NPs were used to detect the presence of cupric ions in water by using the quenching of fluorescence as a transduction signal. In accordance with the spectral overlaps and the values of the critical distance (R0) of D, and A,copper complex pairs, the acceptor is much more sensitive than the donor. In dual fluorescent NPs, the sensitized emission of A is efficiently attenuated whereas the remaining emission of D is much less affected, allowing the detection of copper in a ratiometric manner upon excitation at a single (D) wavelength. Dual-dye-doped NPs with the highest acceptor loads (23,A -per-NP) were found to be the most sensitive for the detection of copper over a wide range of concentrations (20,nM to 8.5,,M). Owing to its great convenience and modularity, the cascade FRET strategy based on dual fluorescent NPs holds great promise for the design of various sensing nanodevices. [source] PRECLINICAL STUDY: FULL ARTICLE: Tolerance to 3,4-methylenedioxymethamphetamine is associated with impaired serotonin releaseADDICTION BIOLOGY, Issue 3 2010Karen Jones ABSTRACT Tolerance to the behavioural effects of 3,4-methylenedioxymethamphetamine (MDMA) following high dose exposure has been attributed to alterations in serotonergic systems. The present study aimed to determine whether decreased 5-HT release and/or 5-HT2A/C receptor desensitization might play a role in tolerance by measuring the response to selective ligands following MDMA exposure. To this end, the latency to nose poke and emerge from a hide box to an open field arena following administration of various ligands to MDMA pre-treated and control rats was measured. Acute exposure to MDMA (0.0,3.3 mg/kg), the 5-HT releasing stimulant fenfluramine (0.0,2.0 mg/kg) and the 5-HT2 receptor agonist m-CPP (0.0,1.25 mg/kg) increased nose poke and emergence latency. Following administration of doses that produce 5-HT2A receptor-mediated behaviours, the 5-HT2 receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane failed to alter nose poke and emergence latency, suggesting a limited role of this receptor subtype in these behaviours. Activation of 5-HT2C receptors was implicated in the behavioural response to both MDMA and m-CPP since the increased emergence latency was dose-dependently attenuated by pre-treatment with the selective 5-HT2C receptor antagonist RS102221 (0.0,1.0 mg/kg). Tolerance to the behavioural effect of MDMA and fenfluramine but not m-CPP was produced by prior exposure to MDMA (10 mg/kg administered at two-hour intervals, total 40 mg/kg), and tissue levels of 5-HT and 5-HIAA were decreased. These findings suggest that tolerance to the increased nose poke and emergence latency produced by MDMA is due to impaired 5-HT release. [source] The sodium pump ,1 sub-unit: a disease progression,related target for metastatic melanoma treatmentJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009Véronique Mathieu Abstract Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump , sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump ,1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis-resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump , sub-units in melanoma clinical samples and cell lines and also to characterize the role of ,1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump , sub-units. In vitro cytotoxicity of various cardenolides and of an anti-,1 siRNA was evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Our data show that all investigated human melanoma cell lines expressed high levels of the ,1 sub-unit, and 33% of human melanomas displayed significant ,1 sub-unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumour effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti-tumour activity in the aggressive human metastatic brain melanoma model in vivo. The ,1 sodium pump sub-unit could represent a potential novel target for combating melanoma. [source] Electrospray ionization mass and tandem mass spectra of a series of N -pyrazolylmethyl and N -triazolylmethyl N -phenylpiperazines: new dopaminergic ligands with potential antipsychotic propertiesJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 6 2005Leonardo S. Santos Abstract Recently, two analogous series of N -pyrazolylmethyl and N -triazolylmethyl N -phenylpiperazines have been prepared and found to be potential antipsychotic drugs acting as new selective ligands of the dopamine D2 receptor. Herein we report a systematic study of their high-resolution electrospray ionization mass and tandem mass spectra in which the main dissociation routes of their protonated molecules are determined and rationalized. The ESI-MS/MS data is very characteristic for both series allowing straightforward isomeric differentiation. A single and dominant fragment ion for the pyrazole series and four major fragment ions for the triazole series are useful for selective reaction MS monitoring of these potential drugs in biological fluids. Copyright © 2005 John Wiley & Sons, Ltd. [source] Acute sleep-promoting action of the melatonin agonist, ramelteon, in the ratJOURNAL OF PINEAL RESEARCH, Issue 2 2008Simon P. Fisher Abstract:, Insomnia, which is severe enough to warrant treatment, occurs in ,10% of the general population. It is associated with a range of adverse consequences for human health, economic productivity and quality of life. In animal and human studies, administration of melatonin has been reported to promote sleep, although there has been controversy regarding its effectiveness. The present study used a chronically implanted radiotelemetry transmitter to record electroencephalogram (EEG) and electromyogram (EMG) to enable discrimination of wake (W), nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in un-restrained rats. The acute action of melatonin and ramelteon, a melatonin agonist recently approved for long-term treatment of insomnia in the USA, was examined. Radioligand binding assays on recombinant human MT1/MT2 receptors showed that both the melatonin and ramelteon were both high affinity, nonsubtype selective ligands. Both compounds acted as potent full agonists on a cellular model of melatonin action, the pigment aggregation response in Xenopus laevis melanophores. Both melatonin and ramelteon (10 mg/kg, i/p), administered close to the mid-point of the dark phase of the L:D cycle, significantly reduced NREM sleep latency (time from injection to the appearance of NREM sleep). Both the drugs also produced a short-lasting increase in NREM sleep duration, but the NREM power spectrum was unaltered. Neither drug altered REM latency, REM sleep duration nor power spectrum during REM sleep. In conclusion, ramelteon administration, like melatonin, exerted an acute, short-lasting sleep-promoting effect in the rat, the model most commonly used to evaluate the activity of novel hypnotic drugs. [source] Ion-dependent gating of kainate receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 1 2010Derek Bowie Ligand-gated ion channels are an important class of signalling protein that depend on small chemical neurotransmitters such as acetylcholine, l -glutamate, glycine and ,-aminobutyrate for activation. Although numerous in number, neurotransmitter substances have always been thought to drive the receptor complex into the open state in much the same way and not rely substantially on other factors. However, recent work on kainate-type (KAR) ionotropic glutamate receptors (iGluRs) has identified an exception to this rule. Here, the activation process fails to occur unless external monovalent anions and cations are present. This absolute requirement of ions singles out KARs from all other ligand-gated ion channels, including closely related AMPA- and NMDA-type iGluR family members. The uniqueness of ion-dependent gating has earmarked this feature of KARs as a putative target for the development of selective ligands; a prospect all the more compelling with the recent elucidation of distinct anion and cation binding pockets. Despite these advances, much remains to be resolved. For example, it is still not clear how ion effects on KARs impacts glutamatergic transmission. I conclude by speculating that further analysis of ion-dependent gating may provide clues into how functionally diverse iGluRs families emerged by evolution. Consequently, ion-dependent gating of KARs looks set to continue to be a subject of topical inquiry well into the future. [source] Ca2+ signalling by P2Y receptors in cultured rat aortic smooth muscle cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2010Sriram Govindan Background and purpose:, P2Y receptors evoke Ca2+ signals in vascular smooth muscle cells and regulate contraction and proliferation, but the roles of the different P2Y receptor subtypes are incompletely resolved. Experimental approach:, Quantitative PCR was used to define expression of mRNA encoding P2Y receptor subtypes in freshly isolated and cultured rat aortic smooth muscle cells (ASMC). Fluorescent indicators in combination with selective ligands were used to measure the changes in cytosolic free [Ca2+] in cultured ASMC evoked by each P2Y receptor subtype. Key results:, The mRNA for all rat P2Y receptor subtypes are expressed at various levels in cultured ASMC. Four P2Y receptor subtypes (P2Y1, P2Y2, P2Y4 and P2Y6) evoke Ca2+ signals that require activation of phospholipase C and comprise both release of Ca2+ from stores and Ca2+ entry across the plasma membrane. Conclusions and implications:, Combining analysis of P2Y receptor expression with functional analyses using selective agonists and antagonists, we isolated the Ca2+ signals evoked in ASMC by activation of P2Y1, P2Y2, P2Y4 and P2Y6 receptors. [source] Prediction of the 3D Structure of FMRF-amide Neuropeptides Bound to the Mouse MrgC11 GPCR and Experimental ValidationCHEMBIOCHEM, Issue 13 2007Jiyoung Heo Dr. Abstract We report the 3D structure predicted for the mouse MrgC11 (mMrgC11) receptor by using the MembStruk computational protocol, and the predicted binding site for the F-M-R-F-NH2 neuropeptide together with four singly chirally modified ligands. We predicted that the R-F-NH2 part of the tetrapeptide sticks down into the protein between the transmembrane (TM) domains 3, 4, 5, and 6. The Phe (F-NH2) interacted favorably with Tyr110 (TM3), while the Arg makes salt bridges to Asp161 (TM4) and Asp179 (TM5). We predicted that the Met extends from the binding site, but the terminal Phe residue sticks back into an aromatic/hydrophobic site flanked by Tyr237, Leu238, Leu240, and Tyr256 (TM6), and Trp162 (TM4). We carried out subsequent mutagenesis experiments followed by intracellular calcium-release assays that demonstrated the dramatic decrease in activity for the Tyr110Ala, Asp161Ala, and Asp179Ala substitutions, which was predicted by our model. These experiments provide strong evidence that our predicted G protein-coupled receptor (GPCR) structure is sufficiently accurate to identify binding sites for selective ligands. Similar studies were made with the mMrgA1 receptor, which did not bind the R-F-NH2 dipeptide; we explain this to be due to the increased hydrophobic character of the binding pocket in mMrgA1. [source] Somatostatin receptor activation (sst1,sst5) differentially influences human retinal pigment epithelium cell viabilityACTA OPHTHALMOLOGICA, Issue 6 2010Thekla Papadaki Abstract. Purpose:, To investigate the differential effects of somatostatin and its receptors (sst1,5) on the viability of cultured human retinal pigment epithelium (hRPE) cells. Methods:, MTT [3 (4, 5-dimethylthiazol-2yl)-2, 5 diphenyltetrazolium bromide], APO PercentageTM and trypan blue assays were performed to assess the mechanisms via which somatostatin (10,10,10,4 m) and selective receptor (sst1,5) ligands (10,12,10,4 m) affect cell viability. The effect of orthovanadate (phosphatase inhibitor, 10,7,10,5 m) on somatostatin's (10,5 m) actions was examined, and western blot analysis was employed to determine the presence of ssts and phosphotyrosine phosphatase SHP-1 in human RPE cells. Results:, Somatostatin and selective ligands for the five somatostatin receptor subtypes (sst1,5) decreased cell viability in a concentration-dependent manner. The observed decrease in cell number was partly because of apoptosis via the activation of sst1 and sst5 receptors. Activation of sst2, sst3 and sst4 receptors led to inhibition of cell growth that did not involve apoptosis, but rather antiproliferative actions. SHP-1 was found in the human RPE cells and sodium orthovanadate reversed somatostatin's actions. Conclusions:, This study provides new information regarding the involvement of ssts in human RPE cell viability and suggests that a pathway involving the phosphotyrosine phosphatase may mediate somatostatin's actions. [source] Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic PotentialCHEMMEDCHEM, Issue 6 2007Novella Romanelli Abstract The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between ,4,2 and ,7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials. [source] | ||||||||||||||||