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Receptor Affinity (receptor + affinity)
Selected AbstractsChemInform Abstract: Synthesis and CB1 Cannabinoid Receptor Affinity of 4-Alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles.CHEMINFORM, Issue 26 2009Hong Shu 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 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 and Opioid Receptor Affinity of a Series of 2,4-Diaryl-Substituted 3,7-Diazabicyclononanones.CHEMINFORM, Issue 10 2001Tom Siener 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, 5-HT1A and 5-HT2A Receptor Affinity of New 1-Phenylpiperazinylpropyl Derivatives of Purine-2,6- and Pyrrolidine-2,5-diones.CHEMINFORM, Issue 3 2001Maciej Pawlowski 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] Time Dependent Effects of Glucocorticoids on Adrenocorticotropin Secretion of Rat Pituitaries Ex-vivoJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2000R. BRUNS Different glucocorticoids have been compared with respect to the inhibition of corticotropin-releasing factor (CRF)-mediated adrenocorticotropin (ACTH) secretion from pituitary fragments of the rat. The influence of time of exposure to glucocorticoids and glucocorticoid concentration has been investigated. CRF-stimulated ACTH secretion of perifused rat pituitary fragments was measured by a chemiluminescence immunoassay. ACTH secretion was monitored over three days. Inhibition of CRF-stimulated ACTH secretion by glucocorticoids was quantified by the area under the curve of CRF-stimulated ACTH secretion over baseline. Concentrations needed to inhibit ACTH secretion decreased with the receptor affinities of the glucocorticoids as follows: fluticasone propionate; receptor affinity 1800, concentration 10,8 M; budesonide, 935 and 3,2.5 times 10,8 M; flunisolide, 478 and 5 times 10,7 M; prednisolone, 10 and 10,6 M. CRF-stimulated secretion was inhibited by glucocorticoids after incubation for 1 min at concentrations between 10,8 and 10,6 M. The same absolute quantity of the glucocorticoids produced no inhibition when incubation was prolonged to 50 min or when a lower concentration was used. Immediately after the perifusion stimulation of ACTH secretion was observed. The results suggest the possibility of minimizing the side effects of glucocorticoids by prolonging drug release. [source] Qualitative difference between the cytotoxic T,lymphocyte responses to melanocyte antigens in melanoma and vitiligoEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2005Belinda Palermo Abstract Vitiligo is a skin disorder characterized by depigmented macules secondary to melanocyte loss. An unusual facet is its relation to melanoma: Cytotoxic T,lymphocytes directed to melanocyte antigens are found in both conditions and imply a breakdown of tolerance, yet the resulting immune reaction is the opposite. The mechanisms at the basis of these opposite effects are not known. Here, we performed a direct comparison of whole melanocyte-specific T,cell populations in the two diseases. We demonstrate that neither precursor frequencies of Melan-A/MART-1-specific T,lymphocytes nor their status of activation differ significantly. However, by using a tetramer-based T,cell receptor down-regulation assay, we documented a higher affinity of vitiligo T,cells. We calculated that the peptide concentration required for 50% of maximal receptor down-regulation differed by 6.5-fold between the two diseases. Moreover, only vitiligo T,cells were capable of efficient receptor down-regulation and IFN-, production in response to HLA-matched melanoma cells, suggesting that this difference in receptor affinity is physiologically relevant. The differences in receptor affinity and tumor reactivity were confirmed by analyzing Melan-A/MART-1-specific clones established from the two diseases. Our results suggest that the quality, and not the quantity, of the melanocyte-specific cytotoxic responses differs between the two pathologies. [source] Synthesis and characterization of 4,6-dichloroindole-based radioligands for imaging the glycine site of the NMDA ion channelJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 2 2002R. N. Waterhouse Abstract To provide effective PET or SPECT ligands for the glycine binding site of the NMDA ion channel, we have synthesized and characterized in vitro four substituted derivatives of the potent glycine site antagonist 3-[2-[(phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid (Ki=3.0 nM). These new ligands contain groups amenable to labeling with C-11 for PET, or I-123 for SPECT. In vitro analysis of these compounds revealed that placement of a methoxy group at either the ortho or para position of the phenylaminocarbonyl group significantly reduced receptor affinity (Ki=74.0±8.1 and 26.5±4.9 nM, respectively), as did placement of an iodine at the para position (Ki=60.4±8.2 nM). However, the meta -methoxy derivative (4b) maintained high affinity (Ki=4.8±0.9 nM) for the glycine site and was therefore labeled with carbon-11 by reacting the corresponding desmethyl derivative with [11C]methyl iodide. Radiochemical yields of 14±10% (EOS), and high specific activity (1.2±0.5 Ci/,mol (EOS, n=7)) were realized, and the product was prepared in a sterile saline solution suitable for in vivo use. Copyright © 2002 John Wiley & Sons, Ltd. [source] Conformation-activity relationships of cyclo -constrained µ/, opioid agonists derived from the N -terminal tetrapeptide segment of dermorphin/deltorphinJOURNAL OF PEPTIDE SCIENCE, Issue 8 2008Sylwia Rodziewicz-Motowid Abstract The N -terminal tetrapeptide segments of dermorphin (Tyr,D -Ala,Phe,Gly,Tyr,Pro,Ser,NH2) and deltorphin (Tyr,D -Ala,Phe,Asp/Glu,Val,Val,Gly,NH2) are agonists at the opioid receptors µ and ,, respectively. [D -Arg2, Lys4]-dermorphin-(1,4) amide (Tyr,D -Arg,Phe,Lys,NH2, DALDA) and [Dmt1]DALDA (where Dmt is 2,,6,-dimethyltyrosine) are among the most potent and selective µ-agonists reported to date, both in vitro (having picomolar µ receptor affinity) and in vivo. In this communication, conformation-activity studies of the following four cyclic analogs of DALDA are presented and discussed: the lead peptide S2,S4 -cyclo (Tyr,D -Cys,Phe,Cys,NH2), constrained by means of an S4.2S4.4 disulfide between Cys2 and Cys4; its two cis and transC4.2C4.4 -olefinic dicarba analogs, and the product of saturation of them both. They are potent nonselective or moderately µ-selective opioid agonists in vitro. They have been synthesized and tested earlier [Berezowska I, Chung NN, Lemieux C, Wilkes BC, and Schiller PW, Acta Biochim Polon 53, 2006, 73,76]. We have studied their conformations using NMR and molecular dynamics. With major conformational constraints imposed by the 11-membered ring spanning residues 2,4, they show well defined conformations of this ring, while the exocylic Tyr1 and Phe3 side chains still have significant conformational freedom. The more active and selective µ versus , disulfide and saturated dicarba agonists seem to have in common: (i) their ring structures more flexilble than those of the other two and (ii) their ring structures similar to each other and more diverse than those in the other two. Given this and the small size of the peptides having confirmed bioactivity profiles, there is a chance that their conformations determined in solution approach receptor-bound conformations. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [source] Human receptor kinetics, tissue binding affinity, and stability of mometasone furoateJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Anagnostis Valotis Abstract Mometasone furoate (MF) is a topically used glucocorticoid with high anti-inflammatory potency. In contrast to the wealth of data derived from clinical studies, information about the molecular pharmacology of the compound is lacking or contradictory. Thus, we elucidated the characteristics of receptor binding kinetics and receptor affinity in a bioassay. Metabolite formation was determined in human plasma and lung tissue as well as binding affinity to human lung tissue. Fast and extensive association of MF to the human glucocorticoid receptor was observed while the dissociation of the MF,receptor complex was faster compared to fluticasone propionate (FP). The relative receptor affinity of MF was calculated as 2200 (dexamethasone,=,100, FP,=,1800) and confirmed in a bioassay measuring the induction of the glucocorticoid regulated protein CD163 in human monocytes. In plasma and human lung tissue MF formed a 9,11-epoxy degradation product. The binding affinity of MF to human lung tissue was low compared to FP due to fast redistribution from tissue into plasma. These molecular pharmacological properties are in accordance with clinical data. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1337,1350, 2004 [source] Time Dependent Effects of Glucocorticoids on Adrenocorticotropin Secretion of Rat Pituitaries Ex-vivoJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2000R. BRUNS Different glucocorticoids have been compared with respect to the inhibition of corticotropin-releasing factor (CRF)-mediated adrenocorticotropin (ACTH) secretion from pituitary fragments of the rat. The influence of time of exposure to glucocorticoids and glucocorticoid concentration has been investigated. CRF-stimulated ACTH secretion of perifused rat pituitary fragments was measured by a chemiluminescence immunoassay. ACTH secretion was monitored over three days. Inhibition of CRF-stimulated ACTH secretion by glucocorticoids was quantified by the area under the curve of CRF-stimulated ACTH secretion over baseline. Concentrations needed to inhibit ACTH secretion decreased with the receptor affinities of the glucocorticoids as follows: fluticasone propionate; receptor affinity 1800, concentration 10,8 M; budesonide, 935 and 3,2.5 times 10,8 M; flunisolide, 478 and 5 times 10,7 M; prednisolone, 10 and 10,6 M. CRF-stimulated secretion was inhibited by glucocorticoids after incubation for 1 min at concentrations between 10,8 and 10,6 M. The same absolute quantity of the glucocorticoids produced no inhibition when incubation was prolonged to 50 min or when a lower concentration was used. Immediately after the perifusion stimulation of ACTH secretion was observed. The results suggest the possibility of minimizing the side effects of glucocorticoids by prolonging drug release. [source] Review article: future therapies for management of metastatic gastroenteropancreatic neuroendocrine tumoursALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11 2009R. SRIRAJASKANTHAN Summary Background, Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are relatively uncommon tumours that occur anywhere within the gastrointestinal tract. The prevalence of GEP NETs is estimated to be 35 per 100 000 population. Patients often present with metastatic disease and consequently, palliative treatments form the mainstay of therapy. Aim, To review the current and novel therapeutic options for management of GEP NETs. Methods, Searches for all studies related to GEP NETs, NETs and carcinoid tumours in Medline and abstracts from international meetings. Results, Somatostatin analogues remain the first line therapy for management of symptoms of GEP NETs and may have anti-proliferative action. New somatostatin analogues with different somatostatin receptor affinity have been developed. Radionuclide peptide receptor therapy is established in patients with positive somatostatin scintigraphy. A number of new agents and targeted therapies are currently being evaluated in a phase I and II studies and these include angiogenic inhibitors, mammalian target of rapamycin inhibitors and immune therapies. Conclusions, A number of nonsurgical therapies are available for management of gastroenteropancreatic neuroendocrine tumours. It is hoped, the development of some of these promising novel therapies will expand the therapeutic armamentarium. [source] Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2006Mireille Canal-Raffin Abstract Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright © 2006 John Wiley & Sons, Ltd. [source] Biological activities of Bv8 analoguesBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2005Lucia Negri The small protein Bv8, secreted by the skin of the frog Bombina variegata, belongs to a novel family of secreted proteins whose orthologues have been identified in snakes (MIT) and in mammals (prokineticins (PKs)). A characteristic feature of this protein family is the same N-terminal sequence, AVITGA, and the presence of 10 cysteines with identical spacing in the C-terminal domain. Two closely related G protein-coupled receptors that mediate signal transduction of Bv8/PKs have been cloned (PK-R1 and PK-R2). In mammals, the Bv8/PK protein family is involved in a number of biological activities such as ingestive behaviours, circadian rhythms, angiogenesis and pain sensitization. In an attempt to identify the structural determinants required for the pronociceptive activity of Bv8, we prepared Bv8 derivatives lacking one (des-Ala- Bv8) or two (des-Ala-Val -Bv8) residues from the N-terminus. des-Ala- Bv8 displayed a receptor affinity five times lower than that of Bv8, it was five times less potent in inducing [Ca2+]i transients and in causing p42/p44 MAPK phosphorylation in CHO-cells expressing PK-R1 and PK-R2. Moreover, dA-Bv8 was about 20 times less potent than Bv8 in inducing hyperalgesia in rats. The deletion of the first two amino acids of Bv8 abolished any biological activity both ,in vitro' and ,in vivo'; however, des-AlaVal -Bv8 is able to antagonize the Bv8-induced hyperalgesia, binding the PK-Rs on peripheral and central projections of the primary sensitive neurons. British Journal of Pharmacology (2005) 146, 625,632. doi:10.1038/sj.bjp.0706376 [source] Separation of cannabinoid receptor affinity and efficacy in delta-8-tetrahydrocannabinol side-chain analoguesBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2001Graeme Griffin The activities of a number of side-chain analogues of delta-8-tetrahydrocannabinol (,8 -THC) in rat cerebellar membrane preparations were tested. The affinities of each compound for the CB1 receptor were compared by their respective abilities to displace [3H]-SR141716A and their efficacies compared by stimulation of [35S]-GTP,S binding. It was found that the affinities varied from 0.19±0.03 nM for 3-norpentyl-3-[6,-cyano,1,,1,-dimethyl]hexyl-,8 -THC to 395±66.3 nM for 5,-[N-(4-chlorophenyl)]-1,,1,-dimethyl-carboxamido-,8 -THC. The efficacies of these compounds varied greatly, ranging from the very low efficacy exhibited to acetylenic compounds such as 1,-heptyn-,8 -THC and 4,-octyn-,8 -THC to higher efficacy compounds such as 5,-(4-cyanophenoxy)-1,,1,-dimethyl-,8 -THC and 5,-[N-(4-aminosulphonylphenyl)]-1,,1, dimethyl-carboxamido ,8 -THC. All agonist activities were antagonized by the CB1 -selective antagonist SR141716A. It was found that a ligand's CB1 affinity and efficacy are differentially altered by modifications in the side-chain. Decreasing the flexibility of the side-chain reduced efficacy but largely did not alter affinity. Additionally, the positioning of electrostatic moieties, such as cyano groups, within the side-chain also has contrasting effects on these two properties. In summary, this report details the characterization of a number of novel ,8 -THC analogues in rat cerebellar membranes. It provides the first detailed pharmacological analysis of how the inclusion of electrostatic moieties in the side-chain and also how alteration of the side-chain's flexibility may differentially affect a CB1 cannabinoid receptor ligand's affinity and efficacy. British Journal of Pharmacology (2001) 132, 525,535; doi:10.1038/sj.bjp.0703827 [source] Silicon Analogues of the RXR-Selective Retinoid Agonist SR11237 (BMS649): Chemistry and BiologyCHEMMEDCHEM, Issue 7 2009W. Peter Lippert Abstract C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4,a (SR11237) and 5,a leads to 4,b (disila-SR11237) and 5,b, respectively. Chemistry and biology of the C/Si pairs are reported. SR11237 (BMS649, 4,a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4,b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5,a and 5,b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4,a/4,b and 5,a/5,b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5,a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5,b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5,a and 5,b, respectively, with the ligand-binding domain of hRXR, and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5,b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design. [source] ,,,-Cyclopentaneglycine Dipeptides Capped with Biaryls as Tachykinin NK2 Receptor AntagonistsCHEMMEDCHEM, Issue 7 2008Marina Porcelloni Dr. Abstract The NK2 receptor belongs to the family of tachykinin neurotransmitters. It has been reported to be involved in several pathological conditions, and selective antagonists are potentially useful drugs for the treatment of asthma, irritable bowel syndrome, cystitis, and depression. Starting from in-house capped dipeptide libraries, we were able to identify a number of molecules with sub-nanomolar binding affinity for the hNK2 receptor. All were characterized by a rigid core structure with a strong constraint induced by an ,,,-cyclopentaneglycine fragment. Herein we report the further elaboration of three initial basic structures. The planar benzothiophene group was substituted with a series of biphenyl and heterobiphenyl moieties that are well tolerated in terms of receptor affinity. The new compounds also maintained good antagonist potency in an in,vitro functional assay, and a number of them showed significant in,vivo activity after intravenous administration in our guinea pig model. [source] Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) and demethyl-ACPA,CHIRALITY, Issue 9 2001Tommy N. Johansen Abstract We have previously described (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of (S)-glutamic acid (Glu) receptors. We now report the chromatographic resolution of ACPA and (RS)-2-amino-3-(3-carboxy-4-isoxazolyl)propionic acid (demethyl-ACPA) using a Sumichiral OA-5000 column. The configuration of the enantiomers of both compounds have been assigned based on X-ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC columns. Furthermore, the enantiopharmacology of ACPA and demethyl-ACPA was investigated using radioligand binding and cortical wedge electrophysiological assay systems and cloned metabotropic Glu receptors. (S)-ACPA showed high affinity in AMPA binding (IC50 = 0.025 ,M), low affinity in kainic acid binding (IC50 = 3.6 ,M), and potent AMPA receptor agonist activity on cortical neurons (EC50 = 0.25 ,M), whereas (R)-ACPA was essentially inactive. Like (S)-ACPA, (S)-demethyl-ACPA displayed high AMPA receptor affinity (IC50 = 0.039 ,M), but was found to be a relatively weak AMPA receptor agonist (EC50 = 12 ,M). The stereoselectivity observed for demethyl-ACPA was high when based on AMPA receptor affinity (eudismic ratio = 250), but low when based on electrophysiological activity (eudismic ratio = 10). (R)-Demethyl-ACPA also possessed a weak NMDA receptor antagonist activity (IC50 = 220 ,M). Among the enantiomers tested, only (S)-demethyl-ACPA showed activity at metabotropic receptors, being a weak antagonist at the mGlu2 receptor subtype (KB = 148 ,M). Chirality 13:523,532, 2001. © 2001 Wiley-Liss, Inc. [source] 4 Hz EMF treated physiological solution depresses Ach-induced neuromembrane currentBIOELECTROMAGNETICS, Issue 5 2004S.N. Ayrapetyan Abstract The effect of 4 Hz EMF treated physiological solution (PS) on acetylcholine (Ach) sensitivity of the snail neuron was studied. The 4 Hz EMF treated normal PS at room temperature (23 °C) has a depressing effect on Ach induced current, while in cold medium (12 °C) this effect disappeared. EMF treated, ouabain containing, K-free PS elevates the Ach-induced current at room temperature. It is suggested that the metabotropic effect of EMF treated PS is due to the activation of cGMP-dependent Na:Ca exchange, leading to the decrease of the number of functional active receptors in the membrane, through Na,K pump-induced cell shrinkage, and to increase the receptors affinity to Ach, as the result of decrease of intracellular Ca concentration. Bioelectromagnetics 25:397,399, 2004. © 2004 Wiley-Liss, Inc. [source] | |||||||||||||