{"search_session":{},"preferences":{"l":"en","queryLanguage":"en"},"patentId":"158-070-037-115-738","frontPageModel":{"patentViewModel":{"ref":{"entityRefId":"158-070-037-115-738","entityRefType":"PATENT"},"entityMetadata":{"linkedIds":{"empty":true},"tags":[],"collections":[{"id":11665,"type":"PATENT","title":"University of Nottingham - Patent Portfolio","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":2682,"tags":[],"user":{"id":91044780,"username":"Cambialens","firstName":"","lastName":"","created":"2015-05-04T00:55:26.000Z","displayName":"Cambialens","preferences":"{\"usage\":\"public\",\"beta\":false}","accountType":"PERSONAL","isOauthOnly":false},"notes":[{"id":8329,"type":"COLLECTION","user":{"id":91044780,"username":"Cambialens","firstName":"","lastName":"","created":"2015-05-04T00:55:26.000Z","displayName":"Cambialens","preferences":"{\"usage\":\"public\",\"beta\":false}","accountType":"PERSONAL","isOauthOnly":false},"text":"
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i) priming a cell or cell material with a sensor for a biological response;\n
ii) contacting the compound(s) to be tested with the primed cell or cell material or contacting a cell or cell material which has been contacted with the compound(s) with the primed cell or cell material;\n
iii) simultaneously or subsequently contacting with a fluorescent agonist or a fluorescent neutral antagonist\nwherein the binding of the fluorescent agonist or antagonist and its associated biological response are detected or monitored in the same cell and are distinct allowing separate readout."],"number":1,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 1 wherein if binding of the test compound(s) to the cell or cell material prevents the binding, and thereby prevents fluorescence, of the fluorescent agonist, and if the associated measurable biological response from the cell or cell material is maintained this indicates that the (non-fluorescent) compound(s) is a potential agonist."],"number":2,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 1 wherein if binding of the test compound(s) to the cell or cell material prevents the binding, and thereby fluorescence, of the fluorescent agonist, and if the associated measurable biological response is absent this indicates that the (non-fluorescent) compound(s) is a potential antagonist."],"number":3,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 1 wherein if the test compound inhibits the binding of a fluorescent neutral antagonist to a defined receptor in a cell and if an associated decrease in biological response is observed, then the (non-fluorescent) compound is a potential inverse agonist."],"number":4,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 1 wherein if the test compound inhibits the binding of a fluorescent neutral antagonist to a defined receptor in a cell and if no associated change in biological response is observed, then the (non-fluorescent) compound is a potential neutral antagonist."],"number":5,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 1 wherein if the test compound inhibits the binding of a fluorescent neutral antagonist to a defined receptor in a cell and if an associated increase in biological response is observed, then the (non-fluorescent) compound is a potential agonist."],"number":6,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 4 wherein the binding of a fluorescent neutral antagonist is to be inhibited, and the assay is conducted in a constitively active receptor system, wherein a receptor is overexpressed, in which the cellular biological response will produce a stimulated response in the absence of any added agonist, antagonist or compound to be tested,"],"number":7,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 further comprising a readout of information relating to morphology of cells, gene transcription or toxicity."],"number":8,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein the binding of the fluorescent agonist is detected with one particular fluorescent wavelength and its associated biological response is monitored in the same cell by a separate readout (e.g. different fluorescent, bioluminescent or chemiluminescent response)."],"number":9,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 for the pharmacological analysis of ligands for drug targets where the ligands are G-protein-coupled receptors (GPCR), ion channels, tyrosine kinase receptors or intracellular receptors including steroid receptors, PPARs (peroxisome proliferation activated receptor)."],"number":10,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 conducted in ultra-high-throughput assays involving multiwell plates or in plasma membrane microdomains of a single living cell."],"number":11,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein inhibition or binding is direct or indirect, and one or more compounds inhibit or bind a cell or cell material which interacts with the primed cell or cell material thereby eliciting or suppressing a response from the primed cell or cell material."],"number":12,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein the detection of a sensor response indicates the one or more compounds is an agonist, and in contrast the suppression of a sensor response indicates the one or more compounds is an antagonist or the detection of a reduced basal sensor response indicates that one or more compounds is an inverse agonist."],"number":13,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 13 wherein the detection of fluorescent agonist fluorescence indicates the one Or more compounds does not inhibit binding of the cell or cell material by the fluorescent agonist and in contrast the suppression of fluorescent agonist fluorescence indicates the one or more compounds inhibits binding of the cell or cell material by the fluorescent agonist."],"number":14,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 which is homogeneous, conducted in a single phase."],"number":15,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 which is non-homogeneous, and requires isolation of assayed material from unbound reagent to achieve a clean readout or signal, wherein the assay employs fluorescent ligands which have affinity such that they bond permanently, semi-permanently or transiently, and remain bound when unbound ligand is washed away, allowing the use of non-homogeneous assay."],"number":16,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 as wherein a sensor is a fluorescent, chemiluminescent or luminescent entity or a reporter gene which is sensitive to a biological response to be investigated, including a fluorescent or luminescent dye which is pH sensitive or voltage sensitive."],"number":17,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 17 wherein a sensor is a fluorescent dye of different wavelength to the fluorescent agonist enabling spectral resolution of the sensor and agonist."],"number":18,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein a fluorescent agonist is any fluorescent agonist whose pharmacological properties are known."],"number":19,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein a fluorescent agonist or fluorescent neutral antagonist is identified by a method for determining the functional response or pharmacological properties of a fluorescent ligand, comprising:\n
a) priming a cell or cell material with a sensor for a biological response;\n
b) subsequently contacting with a fluorescent ligand wherein the binding of the fluorescent ligand and its associated biological response are detected or monitored in the same cell and are distinct allowing separate readout, and wherein if binding, and thereby fluorescence, of the fluorescent ligand is detected, and if the associated measurable biological response from the cell or cell material is maintained this indicates that the fluorescent ligand is a potential agonist, and if binding, and thereby fluorescence, of the fluorescent ligand is detected but the associated measurable biological response from the cell or the cell material is reduced or is absent, this indicates that the fluorescent ligand is a potential neutral antagonist or inverse agonist."],"number":20,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein the fluorescent ligand comprises one or a plurality of ligand moieties linked to one or a plurality of fluorescent moieties via a linker at a linking site which maintains ligand activity, wherein the ligand moiety is a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter, wherein the fluorescent moiety comprises any red, green, near ir, blue absorbing dyes or other classes of dyes where the dyes are in particular including fluorescein, fluorescein derivatives including FITC, and fluorescein-like molecules such as Oregon Green™ and its derivatives, Texas Red™, 7-nitrobenz-2-oxa-1,3-diazole (NBD) and derivatives thereof, coumarin and derivatives thereof, naphthalene including derivatives of dansyl chloride or its analogues or derivatives, Cascade Blue™, EvoBlue or fluorescent derivatives thereof, pyrenes and pyridyloxazole derivatives, the cyanine dyes, the dyomics (DY dyes and ATTO dyes) and fluorescent derivatives thereof, the Alexafluor dyes and derivatives, BDI dyes including the commercially available Bodipy™ dyes, erythosin, eosin, pyrenes, anthracenes, acridines, fluorescent phycobiliproteins and their conjugates and fluoresceinated microbeads, Rhodamine and fluorescent derivatives thereof including Rhodamine Green™ including the tetramethylrhodamines, X-rhodamines and Texas Red derivatives, and Rhodol Green™, coupled to amine groups using the isocyanate, succinimidyl ester or dichlorotriazinyl-reactive groups."],"number":21,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein a GPCR ligand moiety in a fluorescent ligand of the invention is any compound which is active as an agonist for an adenosine receptor, a beta-adrenoceptor, a muscarinic receptor, a histamine receptor, an opiate receptor, a cannabinoid receptor, a chemokine receptor, an alpha-adrenoceptor, a GABA receptor, a prostanoid receptor, a 5-HT (serotonin) receptor, an excitatory aminoacid receptor (eg glutamate), a dopamine receptor, a protease-activating receptor, a neurokinin receptor, an angiotensin receptor, an oxytocin receptor, a leukotriene receptor, a nucleotide receptor (purines and pyrimidines), a calcium-sensing receptor, a thyroid-stimulating hormone receptor, a neurotensin receptor, a vasopressin receptor, an olfactory receptor, a nucleobase receptor (ag adenosine), a lysophosphatidic acid receptor, a sphingolipid receptor, a tyramine receptor (trace amines), a free-fatty acid receptor and a cyclic nucleotide receptor; and an inhibitor of intracellular enzymes in a fluorescent agonist is an inhibitor of cyclic nucleotide phosphodiesterases or a derivative or analogue thereof; and a substrate of a drug transporter in a fluorescent agonist is any drug that is transported into or out of the cell via the transporter and an inhibitor of a drug transporter is any compound which binds to the transporter and prevents a substrate being transported, a substrate or inhibitor of any equilibrium based drug transporters or ATP driven pumps such as a catecholamine transporter, a nucleoside transporter, an ATP-binding cassette transporter or a cyclic nucleotide transporter."],"number":22,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein a fluorescent agonist or antagonist is of the formula\n
\n\nLigJL L JTFl\n\nwhich may be present as a racemate or as one of its optically active isomers wherein Fl is any fluorophore as hereinbefore defined and wherein ligand-linker Lig JL L JT is Lig.a, Lig.b, Lig.c, Lig.d and Lig.h wherein:Lig.a comprises linking functionality JL which is amine, and is of the formula, in either of the following forms given:Lig.a1m \nwherein\n
Ra4 comprises linking functionality JL and JT which is amine;\n
X1 and X2 are each O;\n
R.a3 is H;\n
each of R.a1 and R.a2 is n-propyl;\n
R.a4 is p- substituted phenyl wherein the substituent is heteroalkyl amide amine; and includes L which is a single bond or is C1-50 alkyl, preferably C1-24 alkyl, more preferably C1-12 alkyl optionally substituted by C1 alkyl and including the formula —(CH2), where n is 3 to 8, optionally including one or more heteroatoms —O;\nLig.b comprises linking functionality JL which is amine, and is\nwherein\n
ring substituents X.b1 and X.b2 are each OH;\n
ring heteroatom X.b3 is —O—;\n
Rb1 is CONHEt or CH2OH;\n
and each of R.b2 and R.b3 is H;\n
Rb4 is H;\n
Rb5 comprises linking functionality JT which is amino, and linker L.b saturated C1-12 aliphatic and C6-24 aromatic, optionally substituted by one or more C1 alkyl and optionally including one or more heteroatoms O or cyclic groups;\nLig.c comprises linking functionality JL which is amine and is\nas a racemate or as one of its optically active isomers wherein * indicates an optically active centre,Rc1 is m-, p- dihydroxyphenyl; andRc2 comprises linking functionality JT which is amine, and linker L.c which is C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof optionally comprising one or more heteroatoms O or an optionally substituted by C1 aliphatic;or Lig.d comprises a linking functionality JL which is amine and is\nas a racemate or as one of its optically active isomers wherein * indicates an optically active centre,Rd1 is\nand a substituted C1-20 spiro aromatic ring system comprising a single aromatic ring and a heteroaryl and optionally halo substituted; andRd2 comprises linking functionality JT which is amine, and linker L.d is C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof optionally comprising one or more heteroatoms O and optionally substituted by C1 aliphatic; or Rd2 is C1-6 straight chain alkyl including ether O and substituted by C6-10 aryl which is OH and oxo substituted and comprises linker L.d as hereinbefore defined,or Lig.h comprises a linking functionality JL which is amine and is\n
\n\nRhRh1Rh2L.h\n\nwherein Rh is C1-20 hydrocarbyl including one or more heteroary, aryl, cycloaryl, or heterocyclyl optionally together with or substituted by or including one or more heteroatoms or halo such as O, N, or ClRh1 is C0-4 alkylRh2 is a single bond —NRh3—, —H1C(═H2)NH—or\nwherein H1 is NRh3 or O and H2 is —HN, —O or —S and wherein Rh3 is H, or C1-3 alkyl such as CH3 and CN and Rh4 is a single bond, C1-6 ether or etheramideL.h comprises linking functionality JT which is amino, and linker linker L which is selected from C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof optionally comprising one or more heteroatoms O and optionally substituted by C1 aliphatic."],"number":23,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay according to claim 23 wherein R.a4, R.b5 or R.c2 or R.d2 or L.h comprises linking functionality JT which is amino, and linker L.a, L.b, L.c. L.d or L.h selected from (CH2)m wherein m is in the range 2 to 12, preferably 3 to 8 for example 3, 4, 5, 6, 7 or 8 optionally including one or more substituents C1, or JL L JT is mono or polyethylene glycol diamine, or L.a is a single bond; orR.c2 or R.d2 comprises linking functionality JT which is amino, and linker L.c or L d selected from C(CH3)2CH2Ph and mono amino menthane or the structure\nor Rd2 comprises the following OH substituted aryl structure wherein linking functionality JL is shown as amine, Ld is as hereinabove defined and includes JT which is amine:\nor Rh is\nOr Rh2 is HNC(═NRh3)NH, OCH2C(═O)NH, SC(═NH)NH,"],"number":24,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein a fluorescent agonist or a fluorescent neutral antagonist is selected from the formulae in the annexed figures."],"number":25,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 wherein a cell or cell material comprises live cell material, including individual cells or sub cell compartments, selected from GPCRs, ion channels, intracellular enzymes or drug transporters in living cells, membrane containing these proteins, solubilised receptors, enzymes or drug transporters or GPCR arrays."],"number":26,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 1 which includes detecting a change in the intensity, excitation or emission wavelength distribution of fluorescence (single and multi photon), fluorescence lifetime, fluorescence polarisation or a combination thereof."],"number":27,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay as claimed in claim 27 wherein the spectral characteristics of the one or more compounds and the fluorescent agonist are selected to allow optimum two-colour cross-correlation fluorescence correlation spectroscopy or confocal microscopy, which may be single or multiphoton."],"number":28,"annotation":false,"claim":true,"title":false},{"lines":["A novel fluorescent agonist or fluorescent neutral antagonist selected from compounds as listed in the Figures annexed hereto or from the formula\n
\n\nRhRh1Rh2L.h\n\nwherein Rh is selected from C1-20 hydrocarbyl including one or more heteroary, aryl, cycloaryl, heterocyclyl optionally together with or substituted by or including one or more heteroatoms or halo such as O, N. or ClRh1 is selected from C0-4 alkylRh2 is a single bond or is selected from —NRh3—, —H1C(═H2)NH— or\nwherein H1 is NRh3 or O and H2 is selected from —HN, —O and —S and wherein Rh3 is selected from H, C1-3 alkyl such as CH3 and CN and Rh4 is selected from a single bond, C1-6 ether or etheramideL.h comprises linking functionality JT which is amino, and linker linker L which is selected from C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof optionally comprising one or more heteroatoms O and optionally substituted by C1 aliphatic."],"number":29,"annotation":false,"claim":true,"title":false},{"lines":["A novel fluorescent agonist or fluorescent neutral antagonist as claimed in claim 29 wherein Rh is selected from the following structures\nor Rh2 HNC(═NRh3)NH, OCH2C(═O)NH, SC(═NH)NH,"],"number":30,"annotation":false,"claim":true,"title":false},{"lines":["(canceled)"],"number":31,"annotation":false,"claim":true,"title":false},{"lines":["A ligand identified by the HCS assay or with the agonist or antagonist of claim 1 for drug targets selected from G-protein-coupled receptors (GPCRs), ion channels, tyrosine kinase receptors and intracellular. receptors including steroid receptors, PPARs."],"number":32,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 5 wherein the binding of a fluorescent neutral antagonist is to be inhibited, and the assay is conducted in a constitively active receptor system, wherein a receptor is overexpressed, in which the cellular biological response will produce a stimulated response in the absence of any added agonist, antagonist or compound to be tested."],"number":33,"annotation":false,"claim":true,"title":false},{"lines":["A HCS assay of claim 6 wherein the binding of a fluorescent neutral antagonist is to be inhibited, and the assay is conducted in a constitively active receptor system, wherein a receptor is overexpressed, in which the cellular biological response will produce a stimulated response in the absence of any added agonist, antagonist or compound to be tested."],"number":34,"annotation":false,"claim":true,"title":false}]}},"filters":{"npl":[],"notNpl":[],"applicant":[],"notApplicant":[],"inventor":[],"notInventor":[],"owner":[],"notOwner":[],"tags":[],"dates":[],"types":[],"notTypes":[],"j":[],"notJ":[],"fj":[],"notFj":[],"classIpcr":[],"notClassIpcr":[],"classNat":[],"notClassNat":[],"classCpc":[],"notClassCpc":[],"so":[],"notSo":[],"sat":[]},"sequenceFilters":{"s":"SEQIDNO","d":"ASCENDING","p":0,"n":10,"sp":[],"si":[],"len":[],"t":[],"loc":[]}}