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Receptor Ligands (receptor + ligand)
Kinds of Receptor Ligands Selected AbstractsChemInform Abstract: Synthesis and Dopaminergic Properties of the Two Enantiomers of 3-(3,4-Dimethylphenyl)-1-propylpiperidine, a Potent and Selective Dopamine D4 Receptor Ligand.CHEMINFORM, Issue 15 2001Bruno Macchia 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] Predictive 3D-Quantitative Structure-Activity Relationship for A1 and A2A Adenosine Receptor LigandsMOLECULAR INFORMATICS, Issue 11-12 2009Olga Yuzlenko Abstract The use of QSAR applications to develop adenosine receptor (AR) antagonists is not so common. A library of all xanthine derivatives, obtained at the Department of Technology and Biotechnology of Drugs, was created. Sixty-three active adenosine A1 receptor ligands and one hundred thirty nine active adenosine A2A receptor ligands were used for 3D-QSAR investigation. The 3D-QSAR equations with a high predictive power in estimating the binding affinity values of potential A1 and A2A ARs ligands were derived. For the first time, hybrid shape-property descriptors were used in 3D-QSAR for xanthine ARs ligands. The obtained models were characterized by a high regression and cross-validation coefficients. Two types of the model validation were tested , dividing the library into the training set for model development and external set for model validation and increasing the number of library components and checking the model by cross-validated regression coefficient. The analysis of the results depicts that for the A1 AR binding activity it is important for ligands to possess R1 -propyl substituents along with the phenyl or benzyl substituents bearing halogen atom and phenethyl moiety. For A2A AR affinity it could be favorable to introduce phenethyl or phenyl substituent connected with the tricyclic ring by the alkoxy chain. The nature of R1 group may not significantly affect the A2A AR affinity. High predictive power of the equations suggests their use for further development of adenosine receptor antagonists within xanthine derivatives. [source] Novel Fused Pyrrole Heterocyclic Ring Systems as Structure Analogs of LE 300: Synthesis and Pharmacological Evaluation as Serotonin 5-HT2A, Dopamine and Histamine H1 Receptor LigandsARCHIV DER PHARMAZIE, Issue 2 2010Sherif A. F. Rostom Abstract LE 300 represents a structurally novel type of antagonists acting preferentially at the dopamine D1/D5 receptors and the serotonin 5-HT2A receptor. This compound consists of a ten-membered central azecine ring fused to an indole ring on one side and a benzene moiety on the other side. To estimate the importance of the indole and / or phenyl moieties in this highly active benz-indolo-azecine, both rings were removed and replaced with a 1H -pyrrole counterpart. Accordingly, some new analogs of LE 300 namely, pyrrolo[2,3- g]indolizine, pyrrolo[3,2- a]quinolizine rings and their corresponding dimethylpyrrolo[2,3- d]azonine, and dimethylpyrrolo[2,3- d]azecine were synthesized to be evaluated for their activity at the 5-HT2A and dopamine D1, D2L, D4, D5 receptors in relation to LE 300. In addition, their activity at the H1 -histamine receptors was also determined. The results suggested that the rigid pyrrolo[2,3- g]indolizine 7 and pyrrolo[3,2- a]quinolizine 8 analogs lacked biological activity in the adopted three bioassays. However, their corresponding flexible pyrrolo[2,3- d]azonine 11 and pyrrolo[2,3- d]azecine 12 derivatives revealed weak partial agonistic activity and weak antagonistic potency at the serotonin 5-HT2A and histamine H1 receptors, respectively. Meanwhile, they showed no affinity to any of the four utilized dopamine receptors. Variation in ring size did not contribute to a significant influence on the three tested bioactivities. Removal of the hydrophobic moiety (phenyl ring) and replacement of the indole moiety with a 1H -pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine-type compounds. [source] Synthesis and SAR Study of Opioid Receptor Ligands: Mono- and Bis-IndolomorphinansCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2009Fuying Li Mono- and bis-indolomorphinans were synthesized through a multi-step synthetic approach from the alkaloid, thebaine, to further explore the C-ring SAR (structure-activity relationship) of morphinan scaffold. Both mono-indoles displayed good binding affinity and selectivity for the , receptor, with compound 6b possessed the highest Ki value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both , and , receptors, but moderate binding at the , receptor was observed. Functional assays indicated that the newly synthesized mono-indole 6b was ,-agonist, opposite to the ,-antagonist profile of naltrindole. Bisindoles 7a,b were ,-agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes. [source] Synthesis of New 4-Heteroaryl-2-phenylquinolines and Their Pharmacological Activity as NK-2/NK-3 Receptor Ligands.CHEMINFORM, Issue 18 2007Anna Borioni 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] Novel Phomactin Analogues as PAF Receptor Ligands.CHEMINFORM, Issue 44 2005William P. D. Goldring Abstract For Abstract see ChemInform Abstract in Full Text. [source] Design and Evaluation of Novel Nonsteroidal Dissociating Glucocorticoid Receptor Ligands.CHEMINFORM, Issue 5 2005Nilesh Shah Abstract For Abstract see ChemInform Abstract in Full Text. [source] Synthesis of 1-Methyl-5-(pyrazol-3- and -5-yl- and 1,2,4-triazol-3- and 5-yl)-1,2,3,6-tetrahydropyridine Derivatives and Their Evaluation as Muscarinic Receptor Ligands.CHEMINFORM, Issue 39 2003Maria Rosaria Del Giudice Abstract For Abstract see ChemInform Abstract in Full Text. [source] Discovery of a Novel Series of 6-Azauracil-Based Thyroid Hormone Receptor Ligands: Potent, TR, Subtype-Selective Thyromimetics.CHEMINFORM, Issue 23 2003Robert L. Dow Abstract For Abstract see ChemInform Abstract in Full Text. [source] Dopamine/Serotonin Receptor Ligands.CHEMINFORM, Issue 4 2003Part 3. Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: [1,2,4]Triazole Derivatives as 5-HT1A Serotonin Receptor Ligands.CHEMINFORM, Issue 15 2002Maria Concetta Sarva 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] ChemInform Abstract: Design and Pharmacology of Quinuclidine Derivatives as M2 -Selective Muscarinic Receptor Ligands.CHEMINFORM, Issue 33 2001Thomas M. Boehme 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] ChemInform Abstract: Synthesis of 2(3H)-Benzoxazolinone Derivatives as Potential Melatonin Receptor Ligands.CHEMINFORM, Issue 27 2001Said Yous 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] ChemInform Abstract: Design, Synthesis and Binding Properties of Novel and Selective 5-HT3 and 5-HT4 Receptor Ligands.CHEMINFORM, Issue 16 2001Maria Modica 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] Synthesis and Preliminary Biological Evaluation of 2,-Substituted 2-(3,-Carboxybicyclo[1.1.1]pentyl)glycine Derivatives as Group,I Selective Metabotropic Glutamate Receptor LigandsCHEMMEDCHEM, Issue 3 2006Roberto Pellicciari Prof. Abstract The first series of 2,-substituted 2-(3,-carboxybicyclo[1.1.1]pentyl)glycine derivatives, (2R)- and (2S)-(2,,2,-dichloro-3,-carboxybicyclo[1.1.1]pentyl)glycine (10) and (11), and 2-(2,-chloro-3,-carboxybicyclo[1.1.1]pentyl)glycine (12) were synthesized and evaluated as mGluR ligands. Compounds 11 and 12 were shown to be competitive group,I mGluR antagonists. These results are also discussed in light of docking studies with both the active (closed) and inactive (open) conformations of mGluR1. [source] ,9 -Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult ratsEPILEPSIA, Issue 8 2010Andrew J. Hill Summary Purpose:, We assessed the anticonvulsant potential of the phytocannabinoid ,9 -tetrahydrocannabivarin (,9 -THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats. Methods:, ,9 -THCV was applied before (10 ,m,9 -THCV) or during (10,50 ,m,9 -THCV) epileptiform activity induced by Mg2+ -free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of ,9 -THCV on CB1 receptors were examined using [3H]SR141716A competition binding and [35S]GTP,S assays in rat cortical membranes. Effects of ,9 -THCV (0.025,2.5 mg/kg) on pentylenetetrazole (PTZ),induced seizures in adult rats were also assessed. Results:, After induction of stable spontaneous epileptiform activity, acute ,9 -THCV application (,20 ,m) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 ,m,9 -THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, ,9 -THCV acted as a CB1 receptor ligand, displacing 0.5 nm [3H]SR141716A with a Ki,290 nm, but exerted no agonist stimulation of [35S]GTP,S binding. In PTZ-induced seizures in vivo, 0.25 mg/kg ,9 -THCV significantly reduced seizure incidence. Discussion:, These data demonstrate that ,9 -THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor,mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states. [source] Molecular characterization of a human scavenger receptor, human MARCOFEBS JOURNAL, Issue 3 2000Nabil A. Elshourbagy Murine MARCO has been identified recently in subsets of macrophages located in the peritoneum, marginal zone of the spleen, and the medullary cord of lymph nodes, where it has been proposed that it serves as a bacteria-binding receptor. A scavenger receptor family member with an extended collagenous domain, murine MARCO has also been demonstrated in atherosclerotic lesions of susceptible mice. We report here the identification, tissue and chromosomal localization, and pharmacological characterization of human (h)MARCO. hMARCO was identified from a macrophage cDNA library by electronic screening with the murine MARCO sequence. Nucleotide sequence analysis confirmed that the full-length hMARCO clone encoded a 519-amino acid protein sharing 68.5% identity with murine MARCO. RNA blot analysis indicated that the hMARCO transcript is 2.0 kb in length and is predominantly expressed in human lung, liver, and lymph nodes. Radiation hybrid mapping localized hMARCO to chromosome 2q14. Ligand-binding studies of COS cells expressing hMARCO demonstrated significant specific binding of both Escherichia coli and Staphylococcus aureus. In contrast, the hMARCO receptor expressed in COS cells did not specifically bind the scavenger receptor ligand acetylated low-density lipoprotein (LDL), despite its similarity to the elongated collagen-like binding domain of the macrophage scavenger receptor. In addition, acetylated (Ac)LDL and oxidized (Ox)LDL did not inhibit E. coli binding to hMARCO. These data suggest that hMARCO may play an important role in host defense, but it has no obvious role in the accumulation of modified lipoproteins during atherogenesis. [source] The triakontatetraneuropeptide TTN increases [Ca2+]i in rat astrocytes through activation of peripheral-type benzodiazepine receptorsGLIA, Issue 2 2001Pierrick Gandolfo Abstract Astrocytes synthesize a series of regulatory peptides called endozepines, which act as endogenous ligands of benzodiazepine receptors. We have recently shown that one of these endozepines, the triakontatetraneuropeptide TTN, stimulates DNA synthesis in astroglial cells. The purpose of the present study was to determine the mechanism of action of TTN on cultured rat astrocytes. Binding of the peripheral-type benzodiazepine receptor ligand [3H]Ro5-4864 to intact astrocytes was displaced by TTN, whereas its C-terminal fragment (TTN[17,34], the octadecaneuropeptide ODN) did not compete for [3H]Ro5-4864 binding. Microfluorimetric measurement of cytosolic calcium concentrations ([Ca2+]i) with the fluorescent probe indo-1 showed that TTN (10,10 to 10,6 M) provokes a concentration-dependent increase in [Ca2+]i in cultured astrocytes. Simultaneous administration of TTN (10,8 M) and Ro5-4864 (10,5 M) induced an increase in [Ca2+]i similar to that obtained with Ro5-4864 alone. In contrast, the effects of TTN (10,8 M) and ODN (10,8 M) on [Ca2+]i were strictly additive. Chelation of extracellular Ca2+ by EGTA (6 mM) or blockage of Ca2+ channels with Ni2+ (2 mM) abrogated the stimulatory effect of TTN. The calcium influx evoked by TTN (10,7 M) or by Ro5-4864 (10,5 M) was not affected by the N- and T-type calcium channel blockers ,-conotoxin (10,6 M) and mibefradil (10,6 M), but was significantly reduced by the L-type calcium channel blocker nifedipine (10,7 M). Patch-clamp studies showed that, at negative potentials, TTN (10,7 M) induced a sustained depolarization. Reduction of the chloride concentration in the extracellular solution shifted the reversal potential from 0 mV to a positive potential. These data show that TTN, acting through peripheral-type benzodiazepine receptors, provokes chloride efflux, which in turn induces calcium influx via L-type calcium channels in rat astrocytes. GLIA 35:90,100, 2001. © 2001 Wiley-Liss, Inc. [source] Participation of the Fas and Fas ligand systems in apoptosis during atrophy of the rat submandibular glandsINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2007Shigeru Takahashi Summary Most acinar cells and some duct cells undergo apoptosis during atrophy of the submandibular gland. The present study was designed to elucidate whether Fas and its receptor ligand (FasL) are involved during apoptotic atrophy of the gland. The excretory duct of the right submandibular gland of rats was doubly ligated with metal clips from 1 to 14 days for induction of gland atrophy. Control rats were untreated. Fas and FasL expression in the atrophied submandibular gland was detected using immunohistochemistry (IHC) and Western immunoblot. Expression of activated caspase 8 and activated caspase 3 was also detected with IHC. Fas-positive acinar and duct cells and FasL-positive duct cells increased in the atrophic glands at 3 and 5 days after duct ligation when apoptotic cells were commonly observed. Thereafter, Fas- and FasL-positive cells declined in number. Patterns of expression of Fas and FasL using Western immunoblots concurred with the IHC results. Activated caspase 8-positive cells were present at every time interval but peaked at 3 and 5 days following duct ligation. The cells showing immunoreaction for activated caspase 3 first appeared on day 3, with the peak in apoptosis, after which they decreased. The results indicate that the Fas/FasL systems likely play an important role in apoptotic pathways during atrophy of the submandibular gland. [source] A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemiaJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Masahiko Sato Abstract Vitamin D3 analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC50,=,7.1,±,1.6,nM) and induced osteocalcin promoter activity (EC50,=,1.9,±,1.6,nM). VDRM2 was less potent in inducing Ca2+ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC50,=,37,±,12,nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08,µg/kg per day. Hypercalcemia was observed at a dose of 4.6,µg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35,91]. 1,,25-dihydroxyvitamin D3 [1,,25(OH)2D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046,µg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23,µg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1,13, 3.2,7.7, and 3.5,6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. © 2010 American Society for Bone and Mineral Research [source] Synthesis and characterization of dexamethasone-conjugated linear polyethylenimine as a gene carrierJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010Hyunjung Kim Abstract Linear polyethylenimine (25,kDa, LPEI25k) has been shown to be an effective non-viral gene carrier with higher transfection and lower toxicity than branched polyethylenimine (BPEI) of comparable molecular weight. In this study, dexamethasone was conjugated to LPEI25k to improve the efficiency of gene delivery. Dexamethasone is a synthetic glucocorticoid receptor ligand. Dexamethasone-conjugated LPEI25k (LPEI,Dexa) was evaluated as a gene carrier in various cells. Gel retardation assays showed that LPEI,Dexa completely retarded plasmid DNA (pDNA) at a 0.75:1 weight ratio (LPEI/pDNA). LPEI,Dexa had the highest transfection efficiency at a 2:1 weight ratio (LPEI,Dexa/DNA). At this ratio, the size of the LPEI,Dexa/pDNA complex was approximately 125,nm and the zeta potential was 35,mV. LPEI,Dexa had higher transfection efficiency than LPEI and Lipofectamine 2000. In addition, the cytotoxicity of LPEI,Dexa was much lower than that of BPEI (25,kDa, BPEI25k). In conclusion, LPEI,Dexa has a high transfection efficiency and low toxicity and can therefore be used for non-viral gene delivery. J. Cell. Biochem. 110: 743,751, 2010. © 2010 Wiley-Liss, Inc. [source] N -[3-[4-(2-methoxyphenyl) piperaziny-1-yl]propyl]cyclam: synthesized as a potential 5-HT1A receptor ligand and labelled with 99mTc-nitrido coreJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2008Fenglong Wang Abstract This paper reports the synthesis of new potential 5-HT1A receptor ligand N -[3-[4-(2-methoxyphenyl)piperaziny-1-yl]propyl]cyclam (MPPC) and radiolabelling of it with 99mTc-nitrido core. The novel neutral complex 99mTcN-MPPC combines 1,4,8,11-tetraazacyclotetradecane (cyclam) ligand as chelate moiety for 99mTc-nitrido with a 1-(2-methoxyphenyl)piperazine moiety derived from WAY 100635 via a 3-carbon alkyl chain. This provided a reliable and reproducible method for attaching the technetium to the pharmacophore moiety of WAY 100635. 99mTcN-MPPC was prepared by a two-step procedure and the radiochemical purity was found to be greater than 95%. It was hydrophilic and stable for at least 4,h at room temperature. In vivo stability study in normal rats showed that no degradation of 99mTcN-MPPC was found in deproteinated blood samples at 2,h post-injection. This effective 99mTc-labelling strategy for obtaining neutral 99mTc nitrido complexes would be a useful tool to prepare new SPECT agents to image 5-HT1A receptor with cyclam conjugated ligands. Copyright © 2008 John Wiley & Sons, Ltd. [source] Radiosynthesis and in vivo study of [18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine: a promising new sigma-1 receptor ligandJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 8 2005Jun Zhao Abstract The novel sigma-1 receptor PET radiotracer [18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([18F]WLS1.002, [18F]-2) was synthesized (n=6) by heating the corresponding N -ethylmesylate precursor in an anhydrous acetonitrile solution containing [18F]fluoride, Kryptofix K222 and potassium carbonate for 15 min. Purification was accomplished by reverse-phase HPLC methods, providing [18F]-2 in 59±8% radiochemical yield (EOB), with specific activity of 2.89±0.80 Ci/µmol (EOS) and radiochemical purity of 98.3±2.1%. Rat biodistribution studies revealed relatively high uptake in many organs known to contain sigma-1 receptors, including the lungs, kidney, heart, spleen, and brain. Good clearance from normal tissues was observed over time. Blocking studies (60 min) demonstrated high (>80%) specific binding of [18F]-2 in the brain, with reduction also noted in other organs known to express these sites. Copyright © 2005 John Wiley & Sons, Ltd. [source] A non-peptide radioiodinated high affinity melanocortin-4 receptor ligandJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2003Felikss Mutulis Abstract 4-Cyclohexyl-4-[(1,2,4-triazol-1-yl)methyl]piperidine was introduced into stepwise peptide synthesis procedures using Boc chemistry and derivatives of D -4-iodophenylalanine and D -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. A halogen replacement analogue (I-Mex2) of a known high affinity melanocortin-4 receptor selective compound resulted. It showed a subnanomolar affinity when evaluated on the melanocortin-4 receptor in competition with the , -MSH peptide analogue 125I-NDP-MSH. By treatment with hexamethylditin and tetrakis(triphenylphosphine) palladium I-Mex2 was converted to the corresponding trimethylstannyl derivative. In the next step, Na125I was oxidized by an iodobead. Iododestannylation proceeded in the presence of 1 M phosphate buffer, pH 2.5, and the radio-active derivative 125I-Mex2 formed was separated by HPLC at 40% radiochemical yield. Preliminary investigation showed that 125I-Mex2 is useful as a radioligand for melanocortin-4 receptor binding studies. Copyright © 2003 John Wiley & Sons, Ltd. [source] Regioselective F-18 radiolabeling of AM694, a CB1 cannabinoid receptor ligandJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 9 2003Peter G. Willis Abstract [18F]AM694, [1-(5-[18F]fluoropentyl)-1H-indol-3-yl]-(2-iodophenyl)methanone, 1b, a potential radiotracer for imaging of cerebral cannabinoid receptor (CB1), has been synthesized by no-carrier-added regioselective radiofluorination of the corresponding tosylate. [18F]AM694 was obtained in 20% radiochemical yield (non-decay-corrected) with a specific activity of 14 500 mCi/µmol, a radiochemical purity of > 99%, and a chemical purity of 95.5%. Copyright © 2003 John Wiley & Sons, Ltd. [source] 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand in the nervous tissueJOURNAL OF NEUROCHEMISTRY, Issue 2003K. Waku 2-Arachidonoylglycerol (2-AG) is a unique molecular species of monoacylglycerol identified as an endogenous cannabinoid receptor ligand by us and Mechoulam and co-workers (1). We found that 2-AG possesses binding activity toward the cannabinoid receptor in rat brain. We also found that 2-AG induces transient elevation of the intracellular Ca2+ concentration in NG108-15 cells. The response induced by 2-AG was blocked by pretreatment of cells with a cannabinoid CB1 receptor-specific antagonist SR141716A, indicating that CB1 receptor is involved in the response. Based on the results of structure,activity relationship experiments, we concluded that the cannabinoid CB1 receptor in the nervous system is originally and primary a 2-AG receptor. 2-AG was produced and released from nervous tissues following various types of stimulation through enhanced breakdown of arachidonic acid-containing phospholipids such as inositol phospholipids. Physiological and pathophysiological roles of 2-AG in the nervous system will be discussed. [source] Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005Sergio Veiga Abstract The peripheral-type benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell survival. Different forms of brain injury result in induction of the expression of the PBR in the areas of neurodegeneration, mainly in reactive glial cells. The consequences of induction of PBR expression after brain injury are unknown. To test whether PBR may be involved in the regulation of neuronal survival after injury, we have assessed the effect of two PBR ligands, Ro5-4864 and PK11195, on neuronal loss induced by kainic acid in the hippocampus. Systemic administration of kainic acid to male rats resulted in the induction of a reactive phenotype in astrocytes and microglia and in a significant loss of hilar neurons in the dentate gyrus. Administration of Ro5-4864, before the injection of kainic acid, decreased reactive gliosis in the hilus and prevented hilar neuronal loss. In contrast, PK11195 was unable to reduce reactive gliosis and did not protect hilar neurons from kainic acid. These findings suggest that the PBR is involved in control of neuronal survival and gliosis after brain injury and identify this molecule as a potential target for neuroprotective interventions. © 2005 Wiley-Liss, Inc. [source] 1.8 Å structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cellsACTA CRYSTALLOGRAPHICA SECTION D, Issue 5 2009Kausik Chattopadhyay Glucocorticoid-induced TNF receptor ligand (GITRL), a prominent member of the TNF superfamily, activates its receptor on both effector and regulatory T cells to generate critical costimulatory signals that have been implicated in a wide range of T-cell immune functions. The crystal structures of murine and human orthologs of GITRL recombinantly expressed in Escherichia coli have previously been determined. In contrast to all classical TNF structures, including the human GITRL structure, murine GITRL demonstrated a unique `strand-exchanged' dimeric organization. Such a novel assembly behavior indicated a dramatic impact on receptor activation as well as on the signaling mechanism associated with the murine GITRL costimulatory system. In this present work, the 1.8,Å resolution crystal structure of murine GITRL expressed in Drosophila melanogaster S2 cells is reported. The eukaryotic protein-expression system allows transport of the recombinant protein into the extracellular culture medium, thus maximizing the possibility of obtaining correctly folded material devoid of any folding/assembly artifacts that are often suspected with E. coli -expressed proteins. The S2 cell-expressed murine GITRL adopts an identical `strand-exchanged' dimeric structure to that observed for the E. coli -expressed protein, thus conclusively demonstrating the novel quaternary structure assembly behavior of murine GITRL. [source] Expression of the endogenous, nicotinic acetylcholine receptor ligand, SLURP-1, in human colon cancerAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2008A. Pettersson Summary 1,Secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein-1 (SLURP-1) is a recently discovered endogenous ligand at the ,7 subunit of the nicotinic acetylcholine receptors. Previous reports have shown that SLURP-1 is expressed in normal human keratinocytes seemingly with a pro-apoptotic function. Conversely, such expression was markedly attenuated in transformed cells and it was suggested that the molecule could convey protection against malignant transformation. 2,In this study, we demonstrated the mRNA expression (by RT-PCR) and protein expression (by Western blotting and immunocytochemistry) of SLURP-1 in the human colon cancer cell line, HT-29. 3,Furthermore, we demonstrated the expression of SLURP-1 (by immunohistochemistry) in tumour cells of human colon cancer tissue, and, to a greater extent, in immune and smooth muscle cells of adjacent, macroscopically tumour-free colon tissue. 4,The current findings suggest that SLURP-1 participates in the regulation of gut immune functions and motility, as well as possibly playing a role in colon carcinogenesis/cancer progression. [source] 2-Phenylmelatonin: A Partial Agonist at Enteric Melatonin ReceptorsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2000Maria Grazia Santagostino-Barbone The effect of the melatonin receptor ligand, 2-phenylmelatonin, has been assessed in isolated strips of the guinea-pig proximal colon. 2-Phenylmelatonin (0.01 nM-1 ,M) caused a concentration-dependent contractile response. The potency value (,log EC50) was 9.3±1.0. The maximum effect was 25±4% of that elicited by the maximally effective concentration (0.3 ,M) of 5-HT and 43±3% of that by the maximally effective concentration (10 ,M) of melatonin. When used as an antagonist, 2-phenylmelatonin (0.01 nM and 0.1 nM) concentration-dependently inhibited melatonin-induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2-phenylmelatonin concentrations failed to antagonize melatonin-induced response. Prazosin (0.3 ,M), a selective antagonist of melatonin MT3 sites, antagonized melatonin-induced contractions to an extent similar to that induced by 0.01 nM 2-phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 ,M prazosin and 0.01 nM 2-phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2-Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin-induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist. [source] | |||||||||||||||||||||||||||||||